Modulators of acetylcholine receptors

ABSTRACT

Compounds comprising an aza-bicyclic portion and an aromatic portion linked via an optionally oxidized sulphur atom are disclosed. The compounds disclosed are useful for the treatment of dysfunctions of the central and autonomic nervous systems.

CROSS REFERENCE TO RELATED APPLICATIONS

This application is a divisional of U.S. application Ser. No.10/500,516, which is a U.S. National Phase application under 35 U.S.C. §371 of PCT application No. PCT/US02/021296, filed Jul. 29, 2002, whichclaims priority under 35 U.S.C. § 119(e) from U.S. ProvisionalApplication Ser. No. 60/350,152, filed Jan. 17, 2002.

BACKGROUND OF THE INVENTION

The present invention relates to compounds that modulateneurotransmission by promoting the release of neurotransmitters such asacetylcholine, dopamine and norepinephrine. More particularly, thepresent invention relates to thio-bridged aryl compounds that arecapable of modulating acetylcholine receptors and pharmaceuticalcompositions comprising such compounds.

Acetylcholine receptors modulate the release of neurotransmitters suchas for example dopamine, norepinephrine, acetylcholine, and serotoninfrom different brain regions. By such action, acetylcholine receptorsparticipate in the modulation of neuroendocrine function, respiration,mood, motor control and function, focus and attention, concentration,memory and cognition, and the mechanisms of substance abuse. Ligands foracetylcholine receptors have been demonstrated to have effects onattention, cognition, appetite, substance abuse, memory, extrapyramidalfunction, cardiovascular function, pain, and gastrointestinal motilityand function. The distribution of acetylcholine receptors that bindnicotine, i.e., nicotinic acetylcholine receptors, is widespread in thebrain, including being found in the basal ganglia, limbic system,cerebral cortex and mid- and hind-brain nuclei. In the periphery, theirdistribution includes being in muscle, autonomic ganglia, thegastrointestinal tract and the cardiovascular system.

Acetylcholine receptors have been shown to be decreased in the brains ofpatients suffering from Alzheimer's disease or Parkinson's disease,diseases associated with dementia, motor dysfunction and cognitiveimpairment. Such correlations between acetylcholine receptors andnervous system disorders suggest that compounds that modulateacetylcholine receptors will have beneficial therapeutic effects formany human nervous system disorders. Thus, there is a continuing needfor compounds that can modulate the activity of acetylcholine receptors.

Nicotinic acetylcholine receptors (nAChRs) belong to the ligand gatedion channel family of neurotransmitter receptors. In neuronal andperipheral tissue, nAChRs possess a pentameric structure consisting of 5protein subunits surrounding a central ion channel. Five neuromuscularsubunits (α, β, γ, δ, ε), ten peripheral or neuronal α-subunits (α1 toα10), and three peripheral or neuronal β-subunits (β2 to β4) have beenidentified. These subunits combine to form pentameric receptors in threeways: first, with homomeric 5[α] stoichiometry, for example, α7 to α9;second, with heteromeric 2[α]3[β] stoichiometry, for example,combinations of α1 to α6 and β2 to β4 subunits; and third, the 2[α]1[β]1 [δ]1[γ/ε] stoichiometry found in neuromuscular receptors.

Nicotine modulates multiple neuronal, peripheral and neuromuscularsubtypes of nAChRs. While demonstrating beneficial effects in a numberof neuronal diseases mediated by nAChRs, nicotine also demonstrates anumber of undesirable side effects on cardiovascular, gastrointestinaland neuromuscular systems. It will be appreciated that there is a needfor compounds that can selectively modulate a single or specific groupof nAChRs.

It is desired to provide new compounds which selectively modulate theactivity of acetylcholine receptors. In particular, it is desired toprovide compounds that are capable of acting as selective modulators,preferably agonists, of beta 4 subtype nicotinic acetylcholinereceptors. It is also desirable to provide a method of treatment ofdysfunctions of the central and peripheral nervous systems to treat, forexample, dementia, cognitive and conduct disorders including attentiondeficit hyperactivity disorder, neurodegenerative disorders, includingAlzheimers disease, Parkinson's disease and other diseases in whichdegeneration leads to impaired functioning of the sensory or motorsystems, extrapyramidal disorders associated with neuroleptic use,convulsive disorders, epilepsy, cardiovascular disorders, endocrinedisorders, psychotic disorders including schizophrenia and relateddisorders, bipolar disease and obsessive-compulsive disorder, eatingdisorders, sleep-related disorders, affective disorders includingdepression, anxiety, panic states and stress-related disorders,aggression, emesis, pain and hyperalgesic states of inflammatory andneuropathic origins, sleep and sexual disorders and alcohol and drugabuse or states associated with drug withdrawal including smokingcessation.

WO97/19059 discloses substituted aryl compounds capable of modulatingacetylcholine receptors. WO99/32117 discloses similar compounds whereinthe aryl moiety is replaced by a 2- or 4-pyridine moiety. Specifically,it discloses the compound

Other compounds specifically disclosed all possess a linker, usuallymethylene or ethylene, between the S atom and either (or both) of thetwo ring systems shown above. It would be desirable to providealternative compounds to those disclosed in WO97/19059 and WO99/32117.Preferably, such alternatives should exhibit one or more of thefollowing advantages: improved binding to nAChRs, greater modulation ofnAChRs, improved selectivity between different nAChRs and improvedpharmacokinetic properties (e.g. improved bioavailability).

Radl et al (Archiv der Pharmazie, Weinheim, Germany, 2000, 333(5),107-112) discloses the synthesis and analgesic activity of someside-chain modified anpirtoline derivatives including3-(3-chlorophenylthio)-8-methyl-8-azabicyclo[3.2.1]octane and2-chloro-6-(3-(8-methyl-8-azabicyclo[3.2.1]octyl)thio)-pyridine.

EP0398578 discloses 3-phenylthio-8-azabicyclo[3.2.1]octane and3-phenylthio-8-methyl-8-azabicyclo[3.2.1]octane as intermediates in thesynthesis of piperidino and 8-azabicyclo[3.2.1]oct-8-yl alkanols whichare useful for the treatment of CNS disorders.

The present invention provides compounds represented by Formula (I) orpharmaceutically acceptable salts thereof:

wherein:

-   -   R¹ is —H,        -   C₁₋₁₂ alkyl optionally substituted with 1, 2 or 3 groups            independently selected from halogen, hydroxyl, thiol,            C₁₋₄alkoxy or C₁₋₄alkylthio, or        -   aryl-C₁₋₄alkyl;    -   R² is —H,        -   —OH,        -   —NH₂,        -   —NH-Q-V-T, wherein Q is —C(O)—, —C(O)—NH—, —C(O)O—, or            —SO₂—;            -   V is H, aryl, aryl-C₁₋₁₂alkyl, diaryl-C₁₋₁₂alkyl,                lactonyl, or C₁₋₁₈alkyl optionally substituted with                halogen, hydroxyl, C₁₋₄alkoxy, —C(O)OC₁₋₄alkyl,                —OC(O)C₁₋₄alkyl, aryl-C₁₋₄alkoxy, aryloxy, or                SO₂C₁₋₄alkyl; and            -   T is H, halogen, C₁₋₅alkyl, C₁₋₄alkoxy, nitro, aryl,                aryl-C₁₋₄alkyl, or aryloxy unless V is H in which case T                is absent,        -   aryl,        -   -(L)_(a)-Z, wherein L is CH₂, CO, O, NH or N(C₁₋₄alkyl) and            a is 0 or 1;            -   and            -   Z is C₁₋₃alkyl-F, C₀₋₃alkyl-aryl-R⁶, C₀₋₃alkyl-CO—R⁶,                C₀₋₃alkyl-CO—NR⁶ ₂, C₀₋₃alkyl-CO₂—R⁶, C₀₋₃alkyl-SO₂—R⁶,                C₀₋₃alkyl-SO₂—NR⁶ ₂, C₁₋₃alkyl-OR⁶, C₁₋₃alkyl-CN or                C₁₋₃alkyl-NR⁶ ₂, wherein each C₀₋₃alkyl or C₁₋₃alkyl                portion is optionally substituted with from 1 to 6                groups selected from F and C₁₋₅alkyl,        -   linked back to the aromatic ring so as to form a fused            bicyclic compound represented by Formula (Ia)        -    wherein D is O or S; and            -   E is O, S, NR⁵, C(R⁵)₂, O—CR⁵ ₂, NR⁵—CR⁵ ₂, NR⁵—CO, CR⁵                ₂—O, CR⁵ ₂—S(O)_(r), CR⁵ ₂—NR⁵, CR⁵ ₂—CR⁵ ₂, CO—NR⁵, or                CR⁵═CR⁵; or        -   linked back to the aromatic ring so as to form a fused            bicyclic compound represented by Formula (Ib)        -    wherein G is CR⁵ or N; and            -   J is CR⁵ or N;    -   unless X is N in which case R² is absent    -   R³ is H, halogen, C₁₋₄alkyl optionally substituted with from 1        to 3 fluorine atoms, cyano, CF₃, OC₁₋₄alkyl, aryloxy,        arylC₁₋₄alkyl, arylC₁₋₄alkoxy, C₃₋₁₀cycloalkoxy, carboxy,        carbonamido, —CO—NH—C₁₋₄alkyl, aryl, hydroxy, —SO₂NH₂,        —SO₂NHC₁₋₄alkyl, or —C₁₋₄alkyl-OH;    -   R⁴ is H, halogen, C₁₋₄alkyl optionally substituted with from 1        to 3 fluorine atoms, cyano, CF₃, OC₁₋₄alkyl, aryloxy,        arylC₁₋₄alkyl, arylC₁₋₄alkoxy, C₃₋₁₀cycloalkoxy, carboxy,        carbonamido, —CO—NH—C₁₋₄alkyl, aryl, hydroxy, —SO₂NH₂,        —SO₂NHC₁₋₄alkyl, or —C₁₋₄alkyl-OH;    -   R⁵ is each independently H or C₁₋₄alkyl;    -   R⁶ is each independently H, C₁₋₆alkyl, aryl or arylC₁₋₄alkyl,        each of which (except H) may be optionally substituted with from        1 to 3 fluorine atoms;    -   X is C or N;    -   W is C or N;    -   W′ is C or N;    -   Y is C or N;    -   Y′ is C or N;    -   provided that there are no more than two N atoms in the aryl        ring;    -   A is optionally a double bond, (CH₂)_(q) or (CH₂)O(CH₂);    -   m, n, o and p are independently 0, 1, 2 or 3;    -   q is optionally 1, 2 or 3;    -   r is 0, 1 or 2.        provided that    -   when X, W, W′, Y and Y′ are all C, R³ is H, R⁴ is H or Cl        positioned meta to the sulphur atom, A is (CH₂)_(q) and R¹ is        selected from H, unsubstituted C₁₋₄alkyl and unsubstituted        C₃₋₄cycloalkyl; then R² may not be H or —OH, and that    -   when one of X, Y and Y′ is N, R³ is H, R⁴ is H or Cl positioned        meta to the sulphur atom, A is (CH₂)_(q) and R¹ is selected from        H, unsubstituted C₁₋₄alkyl and unsubstituted C₃₋₄cycloalkyl;        then R may not be H or —OH.

In a further embodiment of the present invention:

-   -   R² is —H,        -   —NH₂,        -   —NH-Q-V-T as defined in claim 1,        -   aryl,        -   -(L)_(a)-Z as defined in claim 1,        -   linked back to the aromatic ring so as to form a fused            bicyclic compound represented by Formula (Ia) as defined in            claim 1, or        -   linked back to the aromatic ring so as to form a fused            bicyclic compound represented by Formula (Ib) as defined in            claim 1;    -   unless X is N in which case R² is absent.

In a further embodiment of the present invention:

-   -   R² is —NH-Q-V-T as defined in claim 1,        -   aryl,        -   -(L)_(a)-Z as defined in claim 1,        -   linked back to the aromatic ring so as to form a fused            bicyclic compound represented by Formula (Ia) as defined in            claim 1, or        -   linked back to the aromatic ring so as to form a fused            bicyclic compound represented by Formula (Ib) as defined in            claim 1;    -   unless X is N in which case R² is absent.

In a further embodiment of the present invention:

-   -   R² is —NH-Q-V-T wherein Q is —C(O)—NH—, or —C(O)O—;        -   V is as defined in claim 1; and        -   T is as defined in claim 1;    -    aryl,    -    -(L)_(a)-Z as defined in claim 1,    -    linked back to the aromatic ring so as to form a fused bicyclic        compound represented by Formula (Ia) as defined in claim 1, or    -    linked back to the aromatic ring so as to form a fused bicyclic        compound represented by Formula (Ib) as defined in claim 1;    -    unless X is N in which case R² is absent.

In one embodiment, the present invention provides a sub-group ofcompounds (Group A) represented by formula (II) or pharmaceuticallyacceptable salts thereof:

wherein:

-   -   R¹ is —H; or        -   C₁₋₁₂alkyl optionally substituted with 1, 2 or 3 groups            independently selected from halogen, hydroxyl, thiol,            C₁₋₄alkoxy or C₁₋₄alkylthio; or aryl-C₁₋₄alkyl    -   R² is —H;        -   —OH;        -   —NH₂;        -   —NH-Q-V-T    -   Q is —C(O)—;        -   —C(O)—NH—;        -   —C(O)O—; or        -   —SO₂    -   V is aryl;        -   aryl-C₁₋₁₂alkyl;        -   diaryl-C₁₋₁₂alkyl;        -   lactonyl; or        -   C₁₋₈alkyl optionally substituted with halogen, hydroxyl,            C₁₋₄alkoxy, —C(O)OC₁₋₄alkyl, —OC(O)C₁₋₄alkyl,            aryl-C₁₋₄alkoxy, aryloxy, SO₂C₁₋₄alkyl;    -   T is H;        -   halogen;        -   aryl;        -   aryl-C₁₋₄alkyl; or        -   aryloxy;            unless X is N in which case R² is absent    -   R³ and R⁴ are each independently selected from H, halogen,        C₁₋₄alkyl, cyano, CF₃, OC₁₋₄alkyl, aryloxy, arylC₁₋₄alkoxy,        C₃₋₁₀cycloalkoxy, carboxy, carbonamido, —CO—NH—C₁₋₄alkyl, aryl,        hydroxy, —SO₂NH₂, —SO₂NHC₁₋₄alkyl, —C₁₋₄alkyl-OH;    -   X is C or N;    -   W is C or N, provided that both X and Y are not N;    -   Y is C or N    -   A is optionally a double bond, (CH₂)_(q) or (CH₂)O(CH₂)    -   m, n, o and p are independently 0, 1, 2 or 3    -   q is optionally 1, 2 or 3.

Within Group A, A is preferably a double bond or (CH₂)_(q) and R¹ ispreferably —H; or C₁₋₁₂alkyl optionally substituted with 1, 2 or 3groups independently selected from hydroxyl, thiol, C₁₋₄alkoxy orC₁₋₄alkylthio; or aryl-C₁₋₄alkyl.

Within Group A, R¹ is more preferably H; C₁₋₆alkyl optionallysubstituted with 1 or 2 hydroxyl groups; or aryl-C₁₋₄alkyl. When R¹ isan aryl-C₁₋₄alkyl group, examples of suitable groups are benzyl,p-methoxybenzyl, furanylmethyl, imidazolylmethyl, pyridinylmethyl,thienylmethyl, pyridylmethyl, N-hydroxypyridylmethyl or thiazolylmethyl.

Within Group A, R¹ is more preferably H, methyl, cyclopropylmethyl,2-hydroxyethyl or isobutyl. When R¹ is one of these groups, greaterpotency is generally observed. More preferably, R¹ is a methyl group.

In one embodiment of Group A, R² is H. When R² is H, R³ is preferablycarbonamido (—CONH₂) or —C₁₋₄alkyl-OH and R⁴ is H, C₁₋₄alkyl, CF₃,halogen or cyano (more preferably H, halogen or cyano). More preferablyR³ is carbonamido (—CONH₂) or —C₁₋₄alkyl-OH and R⁴ is methyl, CF₃, Cl orcyano (more preferably Cl or cyano).

In another embodiment of Group A, R² is OH. When R² is OH, R³ and R⁴ arepreferably H, C₁₋₄alkyl, CF₃, cyano or halogen (more preferably H, cyanoor halogen). More preferably R³ is methyl, CF₃, Cl or cyano (morepreferably Cl or cyano) attached to position Y when Y is C.

Generally, within Group A, when R² is of formula —NH-Q-V-T, T ispreferably H and R³ and R⁴ are preferably H, methyl, CF₃, chloro- orcyano (more preferably H, chloro- or cyano).

In another embodiment of Group A, R² is of the formula —NH—SO₂—V-T,wherein V is aryl, —C₁₋₁₂alkyl or aryl-C₁₋₁₂alkyl. In this embodiment ofthe present invention R³ is preferably H, methyl, CF₃, Cl or cyano (morepreferably H, Cl or cyano) and R⁴ is preferably H.

Within Group A, when R² is of formula —NH—SO₂—V-T, preferably V isselected from C₁₋₁₂alkyl, phenyl, naphthyl, thienyl, oxazolyl,isoxazolyl, or phenyl(CH═CH), optionally substituted with 1, 2, 3 or 4substituents selected from:

-   -   —NO₂;    -   halogen;    -   —CF₃;    -   C₁₋₁₂alkoxy;    -   C₁₋₁₂alkylthio;    -   C₁₋₁₂alkyl;    -   C₁₋₄alkylsulfonyl;    -   —CN;    -   —OCF₃;    -   —C(O)OC₁₋₄alkyl;    -   —OCH₂CF₃;    -   —NHC(O) C₁₋₄alkyl.

Within Group A, when R² is of formula —NH—SO₂—V-T, preferably T isselected from H, or diazole, oxazole, isoxazole, phenyl or phenoxy,optionally substituted with 1, 2, 3 or 4 substituents selected from

-   -   —NO₂;    -   halogen;    -   —CF₃;    -   C₁₋₁₂alkoxy;    -   C₁₋₁₂alkylthio;    -   C₁₋₁₂alkyl;    -   C₁₋₄alkylsulfonyl;    -   —CN;    -   —OCF₃;    -   —C(O)OC₁₋₄alkyl;    -   —OCH₂CF₃;    -   —NHC(O)C₁₋₄alkyl.

Within Group A, when R² is of formula —NH—SO₂—V-T, V is more preferablyselected from 3-chloro-4-methylphenyl, 3-chlorophenyl, 3-methoxyphenyl,4-bromophenyl, 4-methoxyphenyl, 4-methylphenyl, naphthyl,2,4,6-trimethylphenyl, phenyl(CH═CH)—, 4-chlorophenyl, 2-chlorophenyl,2,5-dichlorothien-3-yl, 2,5,6-trimethyl-4-methoxyphenyl,4-methoxyphenyl, 2,3,4-trifluorophenyl, 3-cyanophenyl,2-methoxycarbonylthien-3-yl or 4-pentylphenyl (even more preferablyselected from 4-bromophenyl, 4-methoxyphenyl, 4-methylphenyl, naphthyl,2,4,6-trimethylphenyl, phenyl(CH═CH)—, 4-chlorophenyl, 2-chlorophenyl,2,5-dichlorothien-3-yl, 2,5,6-trimethyl-4-methoxyphenyl,4-methoxyphenyl, 2,3,4-trifluorophenyl, 3-cyanophenyl,2-methoxycarbonylthien-3-yl or 4-pentylphenyl) and T is preferably H.

In a further embodiment within Group A, when R² is of formula—NH—SO₂—V-T, T is preferably 2-chloro-5-nitrophenoxy and V is preferablyphenyl.

In an alternative embodiment of Group A, R² is of formula —NH—C(O)—V-Twherein V is selected from

-   -   aryl;    -   aryl-C₁₋₁₂alkyl;    -   diaryl-C₁₋₁₂alkyl;    -   lactonyl; or    -   C₁₋₁₈alkyl optionally substituted with halogen, hydroxyl,        C₁₋₄alkoxy, C(O)OC₁₋₄alkyl, OC(O)C₁₋₄alkyl, aryl-C₁₋₄alkoxy,        aryloxy. In this embodiment of the present invention, R³ is        preferably H, methyl, CF₃, Cl or cyano (more preferably H, Cl or        cyano) and R⁴ is H.

When R² is of formula —NH—C(O)—V-T, preferably V is selected fromC₁₋₁₂alkyl, phenyl, phenyl-C₁₋₁₂alkyl, diphenylmethyl, naphthyl,furanyl, thienyl, diazolyl, pyridinyl, thiazolyl, benzothienyl,fluorenyl, oxazolyl or isoxazolyl, optionally substituted with 1, 2, 3or 4 substituents independently selected from

-   -   —NO₂;    -   halogen;    -   —CF₃;    -   C₁₋₁₂alkoxy;    -   C₁₋₁₂alkylthio;    -   C₁₋₁₂alkyl;    -   C₁₋₄alkylsulfonyl;    -   —CN;    -   —OCF₃;    -   —C(O)O—C₁₋₄alkyl;    -   —OCH₂CF₃.

When R² is of formula —NH—C(O)—V-T, more preferably V is C₁₋₁₂alkyl.

When R² is of formula —NH—C(O)—V-T, preferably T is selected from

-   -   H;    -   halogen; or    -   diazole, oxazole, isoxazole, phenyl, phenoxy or benzodioxanyl        optionally substituted with 1, 2, 3 or 4 substituents selected        from        -   —NO₂;        -   halogen;        -   —CF₃;        -   C₁₋₁₂ alkylthio;        -   C₁₋₁₂ alkoxy;        -   C₁₋₁₂ alkyl;        -   C₁₋₄ alkylsulfonyl;        -   —CN;        -   —OCF₃;        -   —C(O)O—C₁₋₄ alkyl.

When R² is of formula —NH—C(O)—V-T, more preferably T is H.

In an alternative embodiment of Group A, R² is of formula —NH—C(O)NH—V-Twherein V is selected from

-   -   C₁₋₁₈alkyl optionally substituted with halogen, hydroxyl,        C₁₋₄alkoxy, C(O)OC₁₋₄alkyl, OC(O)C₁₋₄alkyl, aryl-C₁₋₄alkoxy or        aryloxy;    -   aryl; or    -   aryl-C₁₋₂alkyl.

When R² is of formula —NH—C(O)NH—V-T, preferably V is selected fromphenyl, phenyl-C₁₋₁₂alkyl or naphthyl optionally substituted with 1, 2,3 or 4 substituents selected from

-   -   —NO₂;    -   halogen;    -   —CF₃;    -   C₁₋₁₂alkylthio;    -   C₁₋₁₂alkoxy;    -   C₁₋₁₂alkyl;    -   C₁₋₄alkylsulfonyl;    -   —CN;    -   —OCF₃;    -   —C(O)O—C₁₋₄alkyl.

When R² is of formula —NH—C(O)NH—V-T, preferably T is H.

In an alternative embodiment of Group A, R² is of formula —NH—C(O)O-V-T,wherein V is selected from

-   -   C₁₋₁₈alkyl optionally substituted with halogen, hydroxyl,        C₁₋₄alkoxy, C(O)OC₁₋₄alkyl, OC(O)C₁₋₄alkyl, aryl-C₁₋₄alkoxy or        aryloxy;    -   aryl; or    -   aryl-C₁₋₁₂ alkyl.

When R² is of formula —NH—C(O)O-V-T, preferably V is selected fromphenyl or phenyl-C₁₋₁₂alkyl optionally substituted with 1, 2, 3 or 4substituents selected from

-   -   —NO₂;    -   halogen;    -   —CF₃;    -   C₁₋₁₂alkylthio;    -   C₁₋₂alkoxy;    -   C₁₋₁₂alkyl;    -   C₁₋₄alkylsulfonyl;    -   —CN;    -   —OCF₃;    -   —C(O)O—C₁₋₄alkyl; or    -   —OCH₂CF₃.

When R² is of formula —NH—C(O)O-V-T, preferably T is H.

In another embodiment, the present invention provides a furthersub-group of compounds (Group B) represented by formula (I) orpharmaceutically acceptable salts thereof:

wherein R² is of formula —NH—C(O)—V-T

wherein V is H, C₁₋₆alkyl, C₃₋₆cycloalkyl, aryl or aryl-C₁₋₁₂alkyl; and

-   -   T is H, halogen, C₁₋₅alkyl, C₁₋₄alkoxy, nitro, aryl,        aryl-C₁₋₄alkyl, or aryloxy unless    -   V is H in which case T is absent.

In a preferred embodiment within Group B, when V is H, C₁₋₆alkyl orC₃₋₆cycloalkyl, preferably T is H unless V is H in which case T isabsent.

In another preferred embodiment within Group B, when V is aryl oraryl-C₁₋₁₂alkyl, preferably T is H, halogen, C₁₋₅alkyl, C₁₋₄alkoxy,nitro, aryl, aryl-C₁₋₄alkyl, or aryloxy. More preferably, V is phenyl,pyridyl, thienyl, thiazolyl, thiadiazolyl, or phenyl-C₁₋₆alkyl; and T isH, halogen, C₁₋₅alkyl, C₁₋₄alkoxy, nitro, aryl, aryl-C₁₋₄alkyl, oraryloxy.

In another embodiment, the present invention provides a furthersub-group of compounds (Group C) represented by formula (I) orpharmaceutically acceptable salts thereof:

wherein

-   -   R¹ is —H,        -   C₁₋₁₂alkyl optionally substituted with 1, 2 or 3 groups            independently selected from halogen, hydroxyl, thiol,            C₁₋₄alkoxy or C₁₋₄alkylthio, or        -   aryl-C₁₋₄alkyl;    -   R² is —NH₂, or        -   —NH-Q-V-T, wherein Q is —C(O)—, —C(O)—NH—, —C(O)O—, or            —SO₂—;            -   V is H, aryl, aryl-C₁₋₁₂alkyl, diaryl-C₁₋₁₂alkyl,                lactonyl, or C₁₋₁₈alkyl optionally substituted with                halogen, hydroxyl, C₁₋₄alkoxy, —C(O)OC₁₋₄alkyl,                —OC(O)C₁₋₄alkyl, aryl-C₁₋₄alkoxy, aryloxy, or                SO₂C₁₋₄alkyl; and            -   T is H, halogen, aryl, aryl-C₁₋₄alkyl, or aryloxy unless                V is H in which case T is absent,    -   R³ is H, halogen, C₁₋₄alkyl optionally substituted with from 1        to 3 fluorine atoms, cyano, CF₃, OC₁₋₄alkyl, aryloxy,        arylC₁₋₄alkyl, arylC₁₋₄alkoxy, C₃₋₁₀cycloalkoxy, carboxy,        carbonamido, —CO—NH—C₁₋₄alkyl, aryl, hydroxy, —SO₂NH₂,        —SO₂NHC₁₋₄alkyl, or —C₁₋₄alkyl-OH;    -   R⁴ is H, halogen, C₁₋₄alkyl optionally substituted with from 1        to 3 fluorine atoms, cyano, CF₃, OC₁₋₄alkyl, aryloxy,        arylC₁₋₄alkyl, arylC₁₋₄alkoxy, C₃₋₁₀cycloalkoxy, carboxy,        carbonamido, —CO—NH—C₁₋₄alkyl, aryl, hydroxy, —SO₂NH₂,        —SO₂NHC₁₋₄alkyl, or —C₁₋₄alkyl-OH;    -   X is C;    -   W is C or N;    -   W′ is C or N;    -   Y is C or N;    -   Y′ is C or N;    -   provided that there are not more than two N atoms in the aryl        ring and provided that at least one of W, W′, Y or Y′ is N;    -   A is optionally a CH═CH double bond, (CH₂)_(q) or (CH₂)O(CH₂);    -   m, n, o and p are independently 0, 1, 2 or 3;    -   q is optionally 1, 2 or 3;    -   r is 0, 1 or 2.

In a preferred embodiment of the compounds of Group C only one of W, W′,Y and Y′ is N.

In one embodiment of the compounds of Group C

-   -   W is C;    -   W′is C;    -   Y′ is C; and    -   Y is N.

In another embodiment of the compounds of Group C

-   -   W is N;    -   W′ is C;    -   Y′is C; and    -   Y is C.

In another embodiment of the compounds of Group C, R² is —NH₂.

In another embodiment of the compounds of Group C

-   -   R² is —NH-Q-V-T, wherein Q is —C(O)—, —C(O)—NH—, —C(O)O—, or        —SO₂—;        -   V is H, aryl, aryl-C₁₋₁₂alkyl, diaryl-C₁₋₁₂alkyl, lactonyl,            or C₁₋₁₈alkyl optionally substituted with halogen, hydroxyl,            C₁₋₄alkoxy, —C(O)OC₁₋₄alkyl, —OC(O)C₁₋₄alkyl,            aryl-C₁₋₄alkoxy, aryloxy, or SO₂C₁₋₄alkyl; and        -   T is H, halogen, aryl, aryl-C₁₋₄alkyl, or aryloxy unless V            is H in which case T is absent.

Within Group C, when R² is —NH-Q-V-T, preferably Q is —SO₂— or —CO—.

In another embodiment, the present invention provides a furthersub-group of compounds (Group D) represented by formula (I) orpharmaceutically acceptable salts thereof:

wherein

-   -   R¹ is —H,        -   C₁₋₁₂alkyl optionally substituted with 1, 2 or 3 groups            independently selected from halogen, hydroxyl, thiol,            C₁₋₄alkoxy or C₁₋₄alkylthio, or aryl-C₁₋₄alkyl;    -   R² is aryl,    -   R³ is H, halogen, C₁₋₄alkyl optionally substituted with from 1        to 3 fluorine atoms, cyano, CF₃, OC₁₋₄alkyl, aryloxy,        arylC₁₋₄alkyl, arylC₁₋₄alkoxy, C₃₋₁₀cycloalkoxy, carboxy,        carbonamido, —CO—NH—C₁₋₄alkyl, aryl, hydroxy, —SO₂NH₂,        —SO₂NHC₁₋₄alkyl, or —C₁₋₄alkyl-OH,    -   R⁴ is H, halogen, C₁₋₄alkyl optionally substituted with from 1        to 3 fluorine atoms, cyano, CF₃, OC₁₋₄alkyl, aryloxy,        arylC₁₋₄alkyl, arylC₁₋₄alkoxy, C₃₋₁₀cycloalkoxy, carboxy,        carbonamido, —CO—NH—C₁₋₄alkyl, aryl, hydroxy, —SO₂NH₂,        —SO₂NHC₁₋₄alkyl, or —C₁₋₄alkyl-OH;    -   X is C,    -   W is C or N;    -   W′ is C or N;    -   Y is C or N;    -   Y′ is C or N;    -   provided that there are no more than two N atoms in the aryl        ring;    -   A is optionally a CH═CH double bond, (CH₂)_(q) or (CH₂)O(CH₂);    -   m, n, o and p are independently 0, 1, 2 or 3;    -   q is optionally 1, 2 or 3;    -   r is 0, 1 or 2.

Within Group D, R² is preferably a C₃ to C₁₂ aromatic or heteroaromaticgroup optionally substituted with one or more substituents selected fromC₁₋₁₂alkyl, C₁₋₁₂alkoxy, thio, C₁₋₁₂alkylthio, carboxy,carboxy(C₁₋₆alkyl), formyl, C₁₋₆alkylcarbonyl, C₁₋₆alkylsulfonyl,C₁₋₆alkylcarbonylalkoxy, nitro, trihalomethyl, trihaloalkoxy,trihalomethoxy, trihalomethyl(C₁₋₆alkyl), hydroxy, hydroxy(C₁₋₆)alkyl,(C₁₋₆alkoxy)carbonyl, amino, C₁₋₆alkylamino, di(C₁₋₆alkyl)amino,aminocarboxy, C₁₋₆alkylaminocarboxy, di(C₁₋₆alkyl)aminocarboxy,aminocarboxy(C₁₋₆)alkyl, C₁₋₆alkylaminocarboxy(C₁₋₆alkyl),di(C₁₋₆alkyl)aminocarboxy(C₁₋₆alkyl), C₁₋₆alkylcarbonylamino,C₁₋₆alkylcarbonyl(C₁₋₆alkyl)amino, halo, C₁₋₆alkylhalo, sulphamoyl,tetrazolyl and cyano.

Within Group D, R² is more preferably phenyl, naphthyl, fluorenyl,thienyl, furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl,isothiazolyl, oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, diazolyl,triazolyl, tetrazolyl, benzothiazolyl, benzimidazolyl, pyrrolinyl,imidazolinyl, pyranyl, pyronyl, pyridyl, pyrazinyl, pyridazinyl,thianaphthyl, benzofuranyl, isobenzofuranyl, benzothienyl,isobenzothienyl, indolyl, oxyindolyl, isoindolyl, indazolyl, indolinyl,7-azaindolyl, azabenzimidazolyl, carbazolyl benzopyranyl, coumarinyl,isocumarinyl, quinolinyl, isoquinolinyl, quinazolinyl, benzoxazinyl,quinoxalinyl, chromenyl, chromanyl, isochromanyl, phthalazinyl,benzodioxolyl, benzodioxanyl, cinnolinyl or carbolinyl optionallysubstituted with one or more substituents selected from C₁₋₁₂alkyl,C₁₋₁₂alkoxy, thio, C₁₋₁₂alkylthio, carboxy, carboxy(C₁₋₆alkyl), formyl,C₁₋₆alkylcarbonyl, C₁₋₆alkylsulfonyl, C₁₋₆alkylcarbonylalkoxy, nitro,trihalomethyl, trihaloalkoxy, trihalomethoxy, trihalomethyl(C₁₋₆alkyl),hydroxy, hydroxy(C₁₋₆)alkyl, (C₁₋₆alkoxy)carbonyl, amino,C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, aminocarboxy, C₁₋₆alkylaminocarboxy,di(C₁₋₆alkyl)aminocarboxy, aminocarboxy(C₁₋₆)alkyl,C₁₋₆alkylaminocarboxy(C₁₋₆alkyl), di(C₁₋₆alkyl)aminocarboxy(C₁₋₆alkyl),C₁₋₆alkylcarbonylamino, C₁₋₆alkylcarbonyl(C₁₋₆alkyl)amino, halo,C₁₋₆alkylhalo, sulphamoyl, tetrazolyl and cyano.

Within Group D, R² is even more preferably phenyl, thienyl, imidazolyl,oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, diazolyl, triazolyl,tetrazolyl, benzothiazolyl, benzimidazolyl, pyridyl, pyrazinyl,pyridazinyl, benzofuranyl, benzothienyl, or quinolinyl optionallysubstituted with one or more substituents selected from C₁₋₁₂alkyl,C₁₋₁₂alkoxy, thio, C₁₋₁₂alkylthio, carboxy, carboxy(C₁₋₆alkyl), formyl,C₁₋₆alkylcarbonyl, C₁₋₆alkylsulfonyl, C₁₋₆alkylcarbonylalkoxy, nitro,trihalomethyl, trihaloalkoxy, trihalomethoxy, trihalomethyl(C₁₋₆alkyl),hydroxy, hydroxy(C₁₋₆)alkyl, (C₁₋₆alkoxy)carbonyl, amino,C₁₋₆alkylamino, di(C₁₋₆alkyl)amino, aminocarboxy, C₁₋₆alkylaminocarboxy,di(C₁₋₆alkyl)aminocarboxy, aminocarboxy(C₁₋₆)alkyl,C₁₋₆alkylaminocarboxy(C₁₋₆alkyl), di(C₁₋₆alkyl)aminocarboxy(C₁₋₆alkyl),C₁₋₆alkylcarbonylamino, C₁₋₆alkylcarbonyl(C₁₋₆alkyl)amino, halo,C₁₋₆alkylhalo, sulphamoyl, tetrazolyl and cyano.

Within Group D, R² is even more preferably phenyl, pyridyl, orbenzofuranyl, optionally substituted with one or more substituentsselected from C₁₋₁₂alkyl, C₁₋₁₂alkoxy, thio, C₁₋₁₂alkylthio, carboxy,carboxy(C₁₋₆alkyl), formyl, C₁₋₆alkylcarbonyl, C₁₋₆alkylsulfonyl,C₁₋₆alkylcarbonylalkoxy, nitro, trihalomethyl, trihaloalkoxy,trihalomethoxy, trihalomethyl(C₁₋₆alkyl), hydroxy, hydroxy(C₁₋₆)alkyl,(C₁₋₆alkoxy)carbonyl, amino, C₁₋₆alkylamino, di(C₁₋₆alkyl)amino,aminocarboxy, C₁₋₆alkylaminocarboxy, di(C₁₋₆alkyl)aminocarboxy,aminocarboxy(C₁₋₆)alkyl, C₁₋₆alkylaminocarboxy(C₁₋₆alkyl),di(C₁₋₆alkyl)aminocarboxy(C₁₋₆alkyl), C₁₋₆alkylcarbonylamino,C₁₋₆alkylcarbonyl(C₁₋₆alkyl)amino, halo, C₁₋₆alkylhalo, sulphamoyl,tetrazolyl and cyano.

In another embodiment, the present invention provides a furthersub-group of compounds (Group E) represented by formula (I) orpharmaceutically acceptable salts thereof:

wherein:

-   -   R¹ is —H,        -   C₁₋₁₂alkyl optionally substituted with 1, 2 or 3 groups            independently selected from halogen, hydroxyl, thiol,            C₁₋₄alkoxy or C₁₋₄alkylthio, or aryl-C₁₋₄alkyl;    -   R² is (L)_(a)-Z, wherein L is O, CO, CH₂, NH or N(C₁₋₄alkyl) and        a is 0 or 1; and        -   Z is C₁₋₃alkyl-F, C₀₋₃alkyl-aryl-R⁶, C₀₋₃alkyl-CO—R⁶,            C₀₋₃alkyl-CO—NR⁶ ₂, C₀₋₃alkyl-CO₂—R⁶, C₀₋₃alkyl-SO₂—R⁶,            C₀₋₃alkyl-SO₂—NR⁶ ₂, C₁₋₃alkyl-OR⁶, C₁₋₃alkyl-CN or            C₁₋₃alkyl-NR⁶ ₂ wherein each C₀₋₃alkyl or C₁₋₃alkyl portion            is optionally substituted with from 1 to 6 groups selected            from F and C₁₋₅alkyl,    -   R³ is H, halogen, C₁₋₄alkyl optionally substituted with from 1        to 3 fluorine atoms, cyano, CF₃, OC₁₋₄alkyl, aryloxy,        arylC₁₋₄alkyl, arylC₁₋₄alkoxy, C₃₋₁₀cycloalkoxy, carboxy,        carbonamido, —CO—NH—C₁₋₄alkyl, aryl, hydroxy, —SO₂NH₂,        —SO₂NHC₁₋₄alkyl, or —C₁₋₄alkyl-OH;    -   R⁴ is H, halogen, C₁₋₄alkyl optionally substituted with from 1        to 3 fluorine atoms, cyano, CF₃, OC₁₋₄alkyl, aryloxy,        arylC₁₋₄alkyl, arylC₁₋₄alkoxy, C₃₋₁₀cycloalkoxy, carboxy,        carbonamido, —CO—NH—C₁₋₄alkyl, aryl, hydroxy, —SO₂NH₂,        —SO₂NHC₁₋₄alkyl, or —C₁₋₄alkyl-OH;    -   R⁶ is each independently H, C₁₋₆alkyl, aryl, or arylC₁₋₄alkyl,        each of which (except H) may be optionally substituted with from        1 to 3 fluorine atoms;    -   X is C;    -   W is C or N,    -   Y is C or N,    -   W′ is C or N,    -   Y′ is C or N,    -   provided that there are no more than two N atoms in the aryl        ring,    -   A is optionally a double bond, (CH₂)_(q) or (CH₂)O(CH₂);    -   m, n, o and p are independently 0, 1, 2 or 3;    -   q is optionally 1, 2 or 3;    -   r is 0, 1 or 2.

In one preferred embodiment of sub-group E, L is CO.

In another preferred embodiment of sub-group E, L is CH₂.

In another preferred embodiment of sub-group E, L is O.

In another preferred embodiment of sub-group E, L is NH or N(C₁₋₄alkyl).

In another preferred embodiment of sub-group E, Z is C₀₋₃alkyl-aryl-R⁶,C₀₋₃alkyl-CO—NR⁶ ₂, C₀₋₃alkyl-CO₂—R⁶, C₁₋₃alkyl-OR⁶ or C₁₋₃alkyl-NR⁶²wherein each C₀₋₃alkyl or C₁₋₃alkyl portion is optionally substitutedwith from 1 to 6 groups selected from F and C₁₋₅alkyl.

In another preferred embodiment of sub-group E, Z is C₀₋₃alkyl-aryl-R⁶wherein aryl is selected from phenyl, naphthyl, fluorenyl, thienyl,furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl,oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, diazolyl, triazolyl,tetrazolyl, benzothiazolyl, benzimidazolyl, pyrrolinyl, imidazolinyl,pyranyl, pyronyl, pyridyl, pyrazinyl, pyridazinyl, thianaphthyl,benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, indolyl,oxyindolyl, isoindolyl, indazolyl, indolinyl, 7-azaindolyl,azabenzimidazolyl, carbazolyl benzopyranyl, coumarinyl, isocoumarinyl,quinolinyl, isoquinolinyl, quinazolinyl, benzoxazinyl, quinoxalinyl,chromenyl, chromanyl, isochromanyl, phthalazinyl, benzodioxolyl,benzodioxanyl, cinnolinyl or carbolinyl optionally, be substituted withone or more substituents selected from C₁ to C₁₂ alkyl (preferably C₁ toC₆ alkyl), C₁ to C₁₂ alkoxy (preferably C₁ to C₆ alkoxy), thio, C₁ toC₁₂ alkylthio (preferably C₁ to C₆ alkylthio), carboxy, carboxy(C₁ toC₆)alkyl, formyl, C₁ to C₆ alkylcarbonyl, C₁ to C₆ alkylsulfonyl, C₁ toC₆ alkylcarbonylalkoxy, nitro, trihalomethyl, trihalo(C₁ to C₆ alkoxy),trihalomethoxy, trihalomethyl(C₁ to C₆ alkyl), hydroxy, hydroxy(C₁ toC₆)alkyl, (C₁ to C₆ alkoxy)carbonyl, amino, C₁ to C₆ alkylamino, di(C₁to C₆ alkyl)amino, aminocarboxy, C₁ to C₆ alkylaminocarboxy, di(C₁ to C₆alkyl)aminocarboxy, aminocarboxy(C₁ to C₆)alkyl, C₁ to C₆alkylaminocarboxy(C₁ to C₆)alkyl, di(C₁ to C₆ alkyl)aminocarboxy(C₁ toC₆)alkyl, C₁ to C₆ alkylcarbonylamino, C₁ to C₆ alkylcarbonyl(C₁ to C₆alkyl)amino, halo, C₁ to C₆ alkylhalo, sulphamoyl, tetrazolyl and cyanoand wherein each C₀₋₃alkyl portion is optionally substituted with from 1to 3 groups selected from F and C₁₋₃alkyl.

In another preferred embodiment of sub-group E, Z is C₁₋₃alkyl-CO—NR⁶ ₂,wherein each C₁₋₃alkyl portion is optionally substituted with from 1 to3 groups selected from F and C₁₋₃alkyl.

In another preferred embodiment of sub-group E, Z is C₁₋₃alkyl-CO₂—R⁶,wherein each C₁₋₃alkyl portion is optionally substituted with from 1 to3 groups selected from F and C₁₋₃alkyl.

In another preferred embodiment of sub-group E, Z is C₁₋₃alkyl-OR⁶wherein each C₁₋₃alkyl portion is optionally substituted with from 1 to3 groups selected from F and C₁₋₃alkyl.

In another preferred embodiment of sub-group E, Z is C₁₋₃alkyl-NR⁶ ₂wherein each C₁₋₃alkyl portion is optionally substituted with from 1 to3 groups selected from F and C₁₋₃alkyl.

Preferably, within Group E, R⁶ is/are each independently H, C₁₋₆alkyl,phenyl, or phenylC₁₋₄alkyl, each of which (except H) may be optionallysubstituted with from 1 to 3 fluorine atoms. More preferably, withinGroup E, R⁶ is/are each independently H, methyl, ethyl, propyl,cyclohexyl, or benzyl, each of which (except H) may be optionallysubstituted with 1, 2 or 3 fluorine atoms.

In another embodiment, the present invention provides a furthersub-group of compounds (Group F¹) represented by formula (I) orpharmaceutically acceptable salts thereof:

wherein:

-   -   R¹ is —H,        -   C₁₋₁₂alkyl optionally substituted with 1, 2 or 3 groups            independently selected from halogen, hydroxyl, thiol,            C₁₋₄alkoxy or C₁₋₄alkylthio, or aryl-C₁₋₄alkyl;    -   R² is linked back to the aromatic ring so as to form a fused        bicyclic compound represented by Formula (Ia)        -    wherein D is O or S; and            -   E is O, S, NR⁵, or C(R⁵)₂,    -   R³ is H, halogen, C₁₋₄alkyl optionally substituted with from 1        to 3 fluorine atoms, cyano, CF₃, OC₁₋₄alkyl, aryloxy,        arylC₁₋₄alkyl, arylC₁₋₄alkoxy, C₃₋₁₀cycloalkoxy, carboxy,        carbonamido, —CO—NH—C₁₋₄alkyl, aryl, hydroxy, —SO₂NH₂,        —SO₂NHC₁₋₄alkyl, or —C₁₋₄alkyl-OH;    -   R⁴ is H, halogen, C₁₋₄alkyl optionally substituted with from 1        to 3 fluorine atoms, cyano, CF₃, OC₁₋₄alkyl, aryloxy,        arylC₁₋₄alkyl, arylC₁₋₄alkoxy, C₃₋₁₀cycloalkoxy, carboxy,        carbonamido, —CO—NH—C₁₋₄alkyl, aryl, hydroxy, —SO₂NH₂,        —SO₂NHC₁₋₄alkyl, or —C₁₋₄alkyl-OH;    -   R⁵ is each independently H or C₁₋₄alkyl;    -   X is C;    -   W is C or N;    -   Y is C or N;    -   Y′ is C or N;    -   provided that there are no more than two N atoms in the aryl        ring,    -   A is optionally a double bond, (CH₂)_(q) or (CH₂)O(CH₂);    -   m, n, o and p are independently 0, 1, 2 or 3;    -   q is optionally 1, 2 or 3;    -   r is 0, 1 or 2.

In one preferred embodiment of sub-group F¹, E is O or NR⁵.

In another preferred embodiment of sub-group F¹, R⁵ is/are eachindependently H or C₁₋₄alkyl.

In another embodiment, the present invention provides a furthersub-group of compounds (Group F²) represented by formula (I) orpharmaceutically acceptable salts thereof:

wherein:

-   -   R¹ is —H,        -   C₁₋₁₂alkyl optionally substituted with 1, 2 or 3 groups            independently selected from halogen, hydroxyl, thiol,            C₁₋₄alkoxy or C₁₋₄alkylthio, or aryl-C₁₋₄alkyl;    -   R² is linked back to the aromatic ring so as to form a fused        bicyclic compound represented by Formula (Ia)        -   wherein D is O or S; and            -   E is O—CR⁵ ₂, NR⁵—CR⁵ ₂, NR⁵—CO, CR⁵ ₂—O, CR⁵                ₂—S(O)_(r), CR⁵ ₂—NR⁵, CR⁵ ₂—CR⁵ ₂, CO—NR⁵, or CR⁵═CR⁵;    -   R³ is H, halogen, C₁₋₄alkyl optionally substituted with from 1        to 3 fluorine atoms, cyano, CF₃, OC₁₋₄alkyl, aryloxy,        arylC₁₋₄alkyl, arylC₁₋₄alkoxy, C₃₋₁₀cycloalkoxy, carboxy,        carbonamido, —CO—NH—C₁₋₄alkyl, aryl, hydroxy, —SO₂NH₂,        —SO₂NHC₁₋₄alkyl, or —C₁₋₄alkyl-OH;    -   R⁴ is H, halogen, C₁₋₄alkyl optionally substituted with from 1        to 3 fluorine atoms, cyano, CF₃, OC₁₋₄alkyl, aryloxy,        arylC₁₋₄alkyl, arylC₁₋₄alkoxy, C₃₋₁₀cycloalkoxy, carboxy,        carbonamido, —CO—NH—C₁₋₄alkyl, aryl, hydroxy, —SO₂NH₂,        —SO₂NHC₁₋₄alkyl, or —C₁₋₄alkyl-OH;    -   R⁵ is each independently H, C₁₋₄alkyl;    -   X is C;    -   W is C or N;    -   Y is C or N;    -   Y′ is C or N;    -   provided that there are no more than two N atoms in the aryl        ring;    -   A is optionally a double bond or (CH₂)_(q) or (CH₂)O(CH₂);    -   m, n, o and p are independently 0, 1, 2 or 3;    -   q is optionally 1, 2 or 3;    -   r is 0, 1 or 2.

In one preferred embodiment of sub-group F², E is O—CR⁵ ₂, NR⁵—CR⁵ ₂,NR⁵—CO, CR⁵ ₂—CR⁵ ₂, or CR⁵═CR⁵. More preferably, E is O—CR⁵ ₂, NR⁵—CO,or CR⁵═CR⁵.

In another preferred embodiment of sub-group F², R⁵ is/are eachindependently H or C₁₋₄alkyl.

In another embodiment, the present invention provides a furthersub-group of compounds (Group G) represented by formula (I) orpharmaceutically acceptable salts thereof:

wherein:

-   -   R¹ is —H,        -   C₁₋₁₂alkyl optionally substituted with 1, 2 or 3 groups            independently selected from halogen, hydroxyl, thiol,            C₁₋₄alkoxy or C₁₋₄alkylthio, or aryl-C₁₋₄alkyl;    -   R² is linked back to the aromatic ring so as to form a fused        bicyclic compound represented by Formula (Ib)        -    wherein G is CR⁵ or N; and            -   J is CR⁵ or N;    -   R³ is H, halogen, C₁₋₄alkyl optionally substituted with from 1        to 3 fluorine atoms, cyano, CF₃, OC₁₋₄alkyl, aryloxy,        arylC₁₋₄alkyl, arylC₁₋₄alkoxy, C₃₋₁₀-cycloalkoxy, carboxy,        carbonamido, —CO—NH—C₁₋₄alkyl, aryl, hydroxy, —SO₂NH₂,        —SO₂NHC₁₋₄alkyl, or —C₁₋₄alkyl-OH;    -   R⁴ is H, halogen, C₁₋₄alkyl optionally substituted with from 1        to 3 fluorine atoms, cyano, CF₃, OC₁₋₄alkyl, aryloxy,        arylC₁₋₄alkyl, arylC₁₋₄alkoxy, C₃₋₁₀cycloalkoxy, carboxy,        carbonamido, —CO—NH—C₁₋₄alkyl, aryl, hydroxy, —SO₂NH₂,        —SO₂NHC₁₋₄alkyl, or —C₁₋₄alkyl-OH;    -   R⁵ is each independently H or C₁₋₄alkyl;    -   X is C;    -   W is C or N;    -   Y is C or N;    -   Y′is C or N    -   provided that there are no more than two N atoms in the aryl        ring;    -   A is optionally a double bond or (CH₂)_(q) or (CH₂)O(CH₂);    -   m, n, o and p are independently 0, 1, 2 or 3;    -   q is optionally 1, 2 or 3;    -   r is 0, 1 or 2.

In a preferred embodiment of sub-group G, each R⁵ is H.

Within Group A, the sum of m, n, o and p is preferably 2. Morepreferably, m and n are 1; o and p are 0.

Within Group A, q is preferably 2.

Within Group A, X, Y and Z are preferably C.

For all embodiments of the present invention (except Group A, for whichr is 0) r is preferably 0 or 2, and most preferably 0.

For all embodiments of the present invention, R¹ is preferably H orC₁₋₃alkyl, more preferably methyl.

For all embodiments of the present invention, A is preferably CH₂,CH₂CH₂ or CH═CH. More preferably, for all embodiments A is CH₂CH₂. Alsopreferred, for all embodiments is when A is CH═CH.

For all embodiments of the present invention, the sum of m, n, o and pis preferably 2. More preferably, m and n are 1; o and p are 0.

For all embodiments of the present invention it is preferred that m andn are 1, o and p are 0 and A is CH₂CH₂ or CH═CH.

For all embodiments of the present invention, R³ is preferably H,halogen, C₁₋₄alkyl, cyano, CF₃, or OC₁₋₄alkyl, and R⁴ is preferably H,halogen, C₁₋₄alkyl, cyano, CF₃, or OC₁₋₄alkyl.

For all embodiments of the present invention, one or both of R³ and R⁴are preferably positioned ortho to the S(O)_(r) moeity.

For all embodiments of the present invention, one or both of R³ and R⁴are preferably halogen, C₁₋₄alkyl, cyano, CF₃, or OC₁₋₄alkyl, morepreferably halogen, cyano, or C₁₋₄alkyl, most preferably halogen,positioned ortho to the S(O)_(r) moeity.

As used herein, the term “alkyl” means a branched or unbranched, cyclicand/or acyclic, saturated or unsaturated (e.g. alkenyl or alkynyl),monovalent or divalent hydrocarbyl radical. Examples of branched alkylgroups are isopropyl, isobutyl, tert-butyl etc. Examples of cyclic alkylgroups are cyclopropyl, cyclobutyl, cyclopentyl, cycohexyl, adamantyletc. Examples of groups containing both cyclic and acyclic alkylmoieties are cyclopropylmethyl, cyclohexylpropyl, adamantylethyl etc.

As used herein, the term “aryl” means a C₃ to C₂₆, preferably C₃ to C₁₂aromatic or heteroaromatic group which may, optionally, be substitutedwith one or more substituents. Aryl substituents are preferably selectedfrom C₁ to C₁₂ alkyl (preferably C₁ to C₆ alkyl), C₁ to C₁₂ alkoxy(preferably C₁ to C₆ alkoxy), thio, C₁ to C₁₂ alkylthio (preferably C₁to C₆ alkylthio), carboxy, carboxy(C₁ to C₆)alkyl, formyl, C₁ to C₆alkylcarbonyl, C₁ to C₆ alkylsulfonyl, C₁ to C₆ alkylcarbonylalkoxy,nitro, trihalomethyl, trihalo(C₁ to C₆ alkoxy), trihalomethoxy,trihalomethyl(C₁ to C₆ alkyl), hydroxy, hydroxy(C₁ to C₆)alkyl, (C₁ toC₆ alkoxy)carbonyl, amino, C₁ to C₆ alkylamino, di(C₁ to C₆ alkyl)amino,aminocarboxy, C₁ to C₆ alkylaminocarboxy, di(C₁ to C₆alkyl)aminocarboxy, aminocarboxy(C₁ to C₆)alkyl, C₁ to C₆alkylaminocarboxy(C₁ to C₆)alkyl, di(C₁ to C₆ alkyl)aminocarboxy(C₁ toC₆)alkyl, C₁ to C₆ alkylcarbonylamino, C₁ to C₆ alkylcarbonyl(C₁ to C₆alkyl)amino, halo, C₁ to C₆ alkylhalo, sulphamoyl, tetrazolyl and cyano.

Examples of aromatic groups are phenyl, naphthyl, fluorenyl, thienyl,furanyl, pyrrolyl, imidazolyl, pyrazolyl, thiazolyl, isothiazolyl,oxazolyl, isoxazolyl, oxadiazolyl, thiadiazolyl, diazolyl, triazolyl,tetrazolyl, benzothiazolyl, benzimidazolyl, pyrrolinyl, imidazolinyl,pyranyl, pyronyl, pyridyl, pyrazinyl, pyridazinyl, thianaphthyl,benzofuranyl, isobenzofuranyl, benzothienyl, isobenzothienyl, indolyl,oxyindolyl, isoindolyl, indazolyl, indolinyl, 7-azaindolyl,azabenzimidazolyl, carbazolyl benzopyranyl, coumarinyl, isocoumarinyl,quinolinyl, isoquinolinyl, quinazolinyl, benzoxazinyl, quinoxalinyl,chromenyl, chromanyl, isochromanyl, phthalazinyl, benzodioxolyl,benzodioxanyl, cinnolinyl and carbolinyl.

Terms such as “aryl-C₁₋₁₂ alkyl group” include groups such as benzyl,4-chlorobenzyl, phenylpropyl, thienylethyl etc. Further, the alkylmoiety in, for example, aryl-C₁₋₁₂ alkyl groups may optionally besubstituted with 1, 2 or 3 substituents selected from halogen, hydroxyl,C₁₋₄ alkoxy or C₁₋₄ alkylthio.

As used herein the term “lactonyl” means any C₁₋₁₈ cyclic ester. Thelactonyl group may be monocyclic or polycyclic.

As used herein, the terms “halogen” or “halo” refer to any one of F, Cl,Br or I.

Compounds of Group A wherein

-   -   R²═OH; and    -   R³=methyl, CF₃, halogen or H;        may be prepared by a procedure exemplified in Reaction Scheme 1.

While Reaction Scheme 1 exemplifies compounds of the present inventionwherein m=n=1, it will be readily apparent to the skilled person thatthe same procedures may be applied to other ring sizes (i.e. when thesum of m, n, o and p is 3 or more).

Thiophenol (1) [commercial or prepared according to Kita Y.; Takeda, Y.;Okuno, T.; Egi, M.; Ito, K.; Kawaguchi, K; Akai, S. Chem. Pharm. Bull.1997, 45(12), 1887-1890 or Zheng, J.; Hanzlik, R. P. Drug Metab. Dispos.1992, 20(5), 688-694], is coupled with carbamate (2) by displacement ofthe leaving group L. Suitable leaving groups will be readily apparent tothe person skilled in the art. Typical leaving groups include iodo,chloro, bromo, mesyl or tosyl. The coupling reaction is preferablyperformed in a dipolar solvent such as methanol, THF or DMF. Morepreferably, the coupling reaction is performed in a 50/50 mixture of THFand DMF. The coupling reaction is preferably promoted by a suitable basesuch as potassium hydroxide, sodium hydride, sodium ethoxide, potassiumcarbonate or DBU. More preferably, the coupling reaction is performed inthe presence of potassium carbonate or sodium hydride. Typically thecoupling reaction may be carried out over a temperature range of from−78 to 150° C. Preferably, the reaction is carried out at a temperaturein the range of from room temperature to 70° C. Reaction times for thecoupling reaction are typically from 10 minutes to 24 hours. Preferredreaction times are in the range of 30 minutes to 12 hours.

Thioether (3) is subsequently converted into compounds of the presentinvention corresponding to the thioether of formula (4). When R¹ ismethyl, compounds of formula (4) may be prepared by reduction using, forexample, lithium aluminium hydride. When R¹ is other than methyl,compounds of formula (4) may be prepared by deprotection of thecarbamate group (usually under acidic conditions) followed by reactionwith a suitable aldehyde or allyl halide.

Reduction with lithium aluminium hydride is typically carried out inether or THF (preferably THF). Preferably, the reduction is carried outat room temperature. Reaction times vary from 10 minutes to up toseveral days. Preferred reaction times are in the range of 12 to 48hours.

Alternatively, when R¹ is other than methyl, the carbamate derivative(3) is deprotected under standard conditions. Typical carbamatedeprotection conditions involve using either protic acids (e.g.trifluoroacetic acid, HCl, HBr) or Lewis acids (e.g. acidchlorides/bromides, tri(m)ethylsilyl triflate). The solvent used istypically water, dichloromethane, dioxane, THF or ether. Preferably, anacid chloride in dioxane is used when the protecting group is tert-butylcarbamate (Boc). Preferably, HBr in water is used when the protectinggroup is ethyl carbamate. Preferably, deprotection is carried out atroom temperature (in the case of Boc-deprotection) or at reflux (in thecase of ethyl carbamate).

Once a free amine has been realised following deprotection, proceduresfor introducing various R¹ groups (wherein R¹ is optionally substitutedC₁₋₁₂ alkyl or aryl-C₁₋₄ alkyl) will be readily apparent to the skilledperson. Generally, displacement of an alkyl halide (or reductivealkylation with an aldehyde) furnishes the desired tertiary amine (4).

Compounds of Group A wherein:

-   -   R¹=methyl;    -   R²=—NH₂ or —NH-Q-V-T; and    -   R³═H

May be prepared by a procedure exemplified in Reaction Scheme 2.

While Reaction Scheme 2 exemplifies compounds of the present inventionwherein m=n=1, it will be readily apparent to the skilled person thatthe same procedures may be applied to other ring sizes (i.e. when thesum of m, n, o and p is 3 or more).

Commercially available 4-aminothiophenol (5) is coupled with amine (6)by displacement of a suitable leaving group L, as outlined above inReaction Scheme 1. The resultant thioether bridged compound (7) is a keyintermediate in the synthesis of compounds of the present invention. Itwill be readily apparent to the person skilled in the art that variousR² groups of general type —NH-Q-V-T may be prepared from compound (7) bystandard procedures known in the art. For example, when:

-   -   (a) Q is —SO₂—, by coupling with a compound of general formula        T-V-SO₂-L′;    -   (b) Q is —CO—, by coupling with a compound of general formula        T-V-CO-L′;    -   (c) Q is —NH—C(O)—, by coupling with a compound of general        formula T-V-N═C═O;    -   (d) Q is —OC(O)—, by coupling with a compound of general formula        T-V-OC(O)-L′ wherein L′ is any suitable leaving group, such as        Cl, Br, or I.

Typically, the coupling reaction which affords compounds of formula (8)is performed in pyridine or an aprotic solvent such as dichloromethanein the presence of a base such as sodium hydride, pyridine,triethylamine or diisopropylamine. Preferably, the coupling is performedat room temperature with reaction times varying from 10 minutes to 24hours, preferably 30 minutes to 12 hours.

Compounds of Group B wherein V is H may be prepared by a procedureexemplified in Reaction Scheme 3.

While Reaction Scheme 3 exemplifies compounds of the present inventionwherein m=n=1, it will be readily apparent to the skilled person thatthe same procedures may be applied to other ring sizes (i.e. when thesum of m, n, o and p is 3 or more).

A mixture of acetic acid and formic acid is heated under reflux forabout 2 hours. To this is added the thioether bridged compound (7)(prepared according to Scheme 2 above) and heating continues for about1.5 hours. The crude mixture may be purified by elution on an SCXcartridge followed by flash chromatography.

Compounds of Group B wherein V is C₁₋₆alkyl, C₃₋₆cycloalkyl, aryl oraryl-C₁₋₁₂alkyl may be prepared by a procedure exemplified in ReactionScheme 4.

While Reaction Scheme 4 exemplifies compounds of the present inventionwherein m=n=1, it will be readily apparent to the skilled person thatthe same procedures may be applied to other ring sizes (i.e. when thesum of m, n, o and p is 3 or more).

A mixture of the thioether bridged compound (7) (prepared according toScheme 2 above), T-V-CO₂H, 1-hydroxybenzotriazole and carbodiimide resinin DMF is stirred at room temperature for about 3 days. The mixture isfiltered then passed through an SCX cartridge to provide the product(9).

Compounds of Group C wherein R² is NH₂ may be prepared by a procedureexemplified in Reaction Scheme 5.

While Reaction Scheme 5 exemplifies compounds of the present inventionwherein m=n=1, and W is N, it will be readily apparent to the skilledperson that the same procedures may be applied to other ring sizes (i.e.when the sum of m, n, o and p is 3 or more) or where Y is N.

Step 1:

A mixture of the ethanethioate (10) and 2-nitro-5-bromopyridine inethanol and aqueous sodium hydroxide is stirred at room temperature forabout 18 hours. The mixture is applied directly to an SCX cartridge andeluted to yield the crude product which may be purified by preparativeLC-MS to provide the nitro-pyridinyl-thio-azabicyclo compound (11).

Step 2:

A mixture of the nitro-pyridinyl-thio-azabicyclo compound (11) and tin(II) chloride dihydrate in ethyl acetate is heated under reflux forabout 4 days and then worked up by quenching with aqueous sodiumhydrogen carbonate solution to provide the aminopyridine product (12).Step 2 may also be achieved by Pd/C catalysed H₂ reduction

It will be readily apparent to the person skilled in the art thatcompounds of Group C wherein R² is —NH-Q-V-T may be prepared fromcompound (12) by standard procedures known in the art. For example,when:

-   -   (e) Q is —SO₂—, by coupling with a compound of general formula        T-V-SO₂-L′;    -   (f) Q is —CO—, by coupling with a compound of general formula        T-V-CO-L′;    -   (g) Q is —NH—C(O)—, by coupling with a compound of general        formula T-V-N═C═O;    -   (h) Q is —OC(O)—, by coupling with a compound of general formula        T-V-OC(O)-L′wherein L′ is any suitable leaving group, such as        Cl, Br, or I.

Compounds of Group D (R² is aryl) may be prepared by a procedureexemplified in Reaction Schemes 6 to 9

While Reaction Schemes 6 to 9 exemplify compounds of the presentinvention wherein m=n=1, it will be readily apparent to the skilledperson that the same procedures may be applied to other ring sizes (i.e.when the sum of m, n, o and p is 3 or more).

The azabicylothiophenol (13) is dissolved in anhydrous THF undernitrogen and cooled to about 0° C. To this is added in one portionsodium tert-butoxide and the solution is stirred for 10 minutes. Theflask is removed from the ice-bath andN-phenyltrifluoromethanesulfonimide added. The solution is stirred atroom temperature for about 16 hours then worked up to provide thetriflate intermediate (14).

The triflate intermediate (14) may be used in any of the threeprocedures shown in Reaction Schemes 7 to 9 below to provide compoundsof Group D.

A mixture of the triflate (14), lithium chloride, triphenylarsine andtris(dibenzylideneacetone)-dipalladium (0) is stirred inN-methylpyrrolidinone under nitrogen. To this is added3-tributylstannylpyridine and the solution heated to 100° C. Thesolution is cooled to room temperature and aqueous sodium hydroxideadded to quench the reaction. The mixture is worked up and purified toyield a Group D compound wherein R² is pyridinyl.

Representative example of a Stille coupling with microwave assistance

Step 1:

A mixture of3-[(4-bromo-2-chlorophenyl)thio]-8-methyl-8-azabicyclo[3.2.1]octane (x)(670 mg), hexamethylditin (696 mg) and tetrakis(triphenylphosphine)palladium (0) (112 mg) in dry toluene (5 ml) under nitrogen is subjectedto microwave irradiation (200 W, 110° C.) in a sealed vessel. Afterevaporation, the crude material was purified on an Isco CombiFlashdevice to yield3-{[2-chloro-4-(trimethylstannyl)phenyl]thio}-8-methyl-8-azabicyclo[3.2.1]octane(570 mg).

Step 2:

A mixture of3-{[2-chloro-4-(trimethylstannyl)phenyl]thio}-8-methyl-8-azabicyclo[3.2.1]octane(y) (153 mg), 2-chloro-5-bromopyridine (67 mg), lithium chloride (45 mg)and tetrakis(triphenylphosphine) palladium (0) (20 mg) in dioxane (1 ml)is subjected to microwave irradiation (200 W, 105° C.) in a sealedvessel. After evaporation, the material is purified by passage throughan SCX cartridge followed by preparative LC-MS to yield3-{[2-chloro-4-(6-chloropyridin-3-yl)phenyl]thio}-8-methyl-8-azabicyclo[3.2.1]octane(27 mg)

To a mixture of the triflate (14), 5-bromopyrimidine, lithium chlorideand tetrakis(triphenylphosphine) palladium (0) under nitrogen is addedhexamethylditin and dioxane. The mixture is heated under reflux and thenpoured into a mixture of aqueous potassium fluoride and ethyl acetate.This mixture is stirred vigorously, passed through a sintered funnel andthe layers separated. The organic phase is worked up and purified toyield a Group D compound wherein R² is pyrimidinyl.

To a mixture of the triflate (14) and phenylboronic acid in DMF is addedfollowed by dichlorobis(triphenylphosphine) palladium (II). The solutionis heated at about 90° C. for about 4 hours, cooled to room temperatureand diluted with ethyl acetate. The reaction mixture is worked up andpurified to a Group D compound wherein R² is phenyl.

Compounds of Group E (R² is (L)_(a)-Z) may be prepared by a procedureexemplified in Reaction Schemes 10 to 13.

While Reaction Schemes 10 to 13 exemplify compounds of the presentinvention wherein m=n=1, it will be readily apparent to the skilledperson that the same procedures may be applied to other ring sizes (i.e.when the sum of m, n, o and p is 3 or more).

Phenol (4) is coupled with a compound of formula Z-X wherein X is asuitable leaving group such halogen, trifluoromethanesulfonyl, tosyl ormesyl and Z is C₁₋₃alkyl-F, C₀₋₃alkyl-aryl-R⁶, C₁₋₃alkyl-CN,C₀₋₃alkyl-CO—R⁶, C₀₋₃alkyl-CO—NR⁶ ₂, C₀₋₃alkyl-CO₂—R⁶, C₀₋₃alkyl-SO₂—R⁶,C₀₋₃alkyl-SO₂NR⁶ ₂, C₁₋₃alkyl-OR⁶ or C₁₋₃alkyl-NR⁶ ₂, wherein eachC₀₋₃alkyl or C₁₋₃alkyl portion is optionally substituted with from 1 to6 groups selected from F and C₁₋₅alkyl.

The coupling reaction is preferably performed in a dipolar solvent suchas ethanol, THF, DMSO, acetonitrile or DMF. More preferably the reactionis performed in DMF or DMSO. The coupling reaction is preferablypromoted by a suitable base such as potassium hydroxide, sodium hydride,sodium ethoxide, cesium carbonate, potassium carbonate, potassiumfluoride, BEMP, polystyrene-supported BEMP or DBU. More preferably, thecoupling reaction is performed in the presence of cesium carbonate,potassium fluoride, sodium hydride or polystyrene-supported BEMP.Typically the coupling reaction may be carried out over a temperaturerange of from −78 to 150° C. Preferably, the reaction is carried out ata temperature in the range of from room temperature to 70° C. Reactiontimes for the coupling reaction are typically from 10 minutes to 24hours. Preferred reaction times are in the range of 30 minutes to 12hours. In some cases microwaves were applied.

Alternatively, some of the above compounds may be used as keyintermediates for other compounds of the subgroup E with methods knownby those skilled in the art.

Phenol (4) is coupled with a compound of formula Z-OH wherein Z isC₁₋₃alkyl-F, C₁₋₃alkyl-aryl-R⁶ wherein the C₁₋₃alkyl portion isoptionally substituted with from 1 to 6 groups selected from F andC₁₋₅alkyl.

A mixture solution of the phenol (4) was treated with the correspondingalcohol derivative, a phosphine derivative and a diazacarboxylatederivative under microwaves conditions in a polar solvent such as DMF at150° C. over 1-4 hours. The reaction mixtures were passed through SCXcartridge eluting with methanol and then 2M ammonia in methanol andconcentrated to dryness. The materials were then further purified bypreparative LC-MS.

Phenol derivative, wherein X is trifluoromethanesulfonyl, iodo, chloroor bromo, is coupled with a compound of formula Z-L-H wherein L is NH orN(C₁₋₄alkyl), Z is C₁₋₃alkyl-F, C₀₋₃alkyl-aryl-R⁶, C₀₋₃alkyl-CN,C₀₋₃alkyl-CO—R⁶, C₀₋₃alkyl-CO—NR⁶ ₂, C₀₋₃alkyl-CO₂—R⁶, C₀₋₃alkyl-SO₂—R⁶,C₀₋₃alkyl-SO₂—NR⁶ ₂, C₁₋₃alkyl-OR⁶ or C₁₋₃alkyl-NR⁶ ₂ wherein eachC₀₋₃alkyl or C₁₋₃alkyl portion is optionally substituted with from 1 to6 groups selected from F and C₁₋₅alkyl.

A derivative of Pd (0), a phosphine ligand and a suitable base suchCsCO₃ were charged in a schlenk flask evacuated and filled with argon.Then the corresponding aryl derivative, more preferably (13), with thedesired amine were added under argon. The reaction was carry out in anorganic solvent such as THF or toluene and the mixture was heating at100° C. overnight. The reaction was concentrated in vacuo and purifiedin SiO₂ to obtain the final compounds.

The intermediate thiobenzene, more preferably triflate (14), is coupledwith compounds M-L-Z by displacement of M using palladium (H) salts as acatalyst and in the presence of phosphines. Suitable palladium (II)salts will be readily apparent to the person skilled in the art. Thecoupling reaction is performed in an organic solvent such as methanol,dioxane, acetonitrile, THF or DMF. Typically the coupling reaction maybe carried out over a temperature range of from 0 to 150° C. Preferably,the reaction is carried out at a temperature in the range of from roomtemperature to 100° C. Reaction times for the coupling reaction are from3 hours to 48 hours.

In this scheme, M is H or metal, X is Cl, Br, I, ortrifluoromethanesulfonyl, L is C₁alkyl and Z is C₁₋₃alkyl-F,C₁₋₃alkyl-aryl-R⁶, C₁₋₃alkyl-CN, C₁₋₃alkyl-CO—R⁶, C₁₋₃alkyl-CO—NR⁶ ₂,C₁₋₃alkyl-CO₂—R⁶, C₁₋₃alkyl-SO₂—R⁶, C₁₋₃alkyl-SO₂—NR⁶ ₂, C₁₋₃alkyl-OR⁶or C₁₋₃alkyl-NR⁶ ₂ wherein the C₁₋₃alkyl portion is optionallysubstituted with from 1 to 6 groups selected from F and C₁₋₅alkyl.

The intermediate thiobenzene, more preferably triflate (14), is coupledwith compounds M-L-Z by displacement of M using palladium (II) salts asa catalyst and in the presence of phosphines. Suitable palladium (II)salts will be readily apparent to the person skilled in the art. Thecoupling reaction is performed in an organic solvent such as methanol,dioxane, acetonitrile, THF or DMF. Typically the coupling reaction maybe carried out over a temperature range of from 0 to 150° C. Preferably,the reaction is carried out at a temperature in the range of from roomtemperature to 100° C. Reaction times for the coupling reaction are from3 hours to 48 hours.

Alternatively, some of the above compounds may be used as keyintermediates for other compounds of the subgroup E with methods knownby those skilled in the art.

Compounds of Group F¹ and F² may be prepared by procedures exemplifiedin Reaction Schemes 14 to 17. While the Schemes exemplify compounds ofthe present invention wherein m=n=1, it will be readily apparent to theskilled person that the same procedures may be applied to other ringsizes (i.e. when the sum of m, n, o and p is 3 or more).

Unsubstituted precursors to compounds of group F¹ and F² (wherein R³═H,R⁴═H, D=O or S and E=O, S, NH, O—CR⁵ ₂, NR⁵—CR⁵ ₂, NR⁵—CO, CR⁵ ₂—O, CR⁵₂—S, CR⁵ ₂—NR⁵, CR⁵ ₂—CR⁵ ₂, CO—NR⁵, or CR⁵═CR⁵) may be treated withexcess chlorosulphonic acid to selectively introduce a chlorosulphonylgroup para to the N—H. The chlorosulphonic acid may be used neat or in asolvent such as chloroform or dichloromethane at a temperature between 0and 100° C. Reduction to the acetylthio compound may be effected withzinc, acetic anhydride and acetic acid at a temperature between 0° C.and ambient temperature. Removal of the acetyl group may be effected bya secondary amine such as pyrollidine and subsequent alkylation of thefree thiol with an appropriate mesylate may be mediated by a base suchas potassium carbonate or cesium fluoride in an aprotic solvent such asdimethylformamide. This reaction is performed between ambienttemperature and 100° C. It will be appreciated by those skilled in theart that exo and endo isomers may be obtained and these can be separatedby crystallisation or chromatography.

An alternative route to aryl thiols is shown in scheme 15 for D=E=O andR³=Me. This utilises 1 equivalent of chlorosulphonic acid at 0° C. andambient temperature to give a sulphonic acid derivative which may bereduced directly to a thiol using iodine and triphenylphosphine in asolvent such as benzene at reflux under Dean and Stark conditions.

Substituted compounds of group F¹ and F² (R³═H, CL, R⁴═H, D=O, S andE=O, S, NR⁵, O —CR⁵ ₂, NR⁵—CR⁵ ₂, NR⁵—CO) may be prepared by a routeexemplified in Scheme 16.

Reaction of a mesylate with potassium thioacetate in an aprotic solventsuch as a mixture of dimethylformamide and tetrahydrofuran attemperatures between ambient and 80° C. gives rise to an acetylthioderivative. It will be appreciated by those skilled in the art that exoand endo isomers may be obtained and these can be separated bychromatography. These compounds may be used to displace a halo atom (egchlorine) from an appropriately substituted nitrophenyl derivative in areaction mediated by a nucleophilic base such as hydroxide at ambienttemperature. The resultant nitro derivative may be reduced by catalytichydrogenation in a protic solvent such as ethanol or by tin chloride inethyl acetate at reflux temperature. Finally reaction with phosgene (ora synthetic equivalent eg triphosgene) or thiophosgene in a solvent suchas dichloromethane or chloroform at a temperature between ambient andreflux temperature gives rise to the compounds of group F¹ and F²specified.

Compounds of Group F² where D=O, E=CR⁵═CR⁵ and R³═R⁴ may be prepared bya procedure exemplified in Reaction Scheme 17.

An acetylthio compound may be used to displace a halo atom (eg chlorine)from an appropriately substituted nitrophenyl derivative in a reactionmediated by a nucleophilic base such as hydroxide at ambienttemperature. The resultant nitro derivative may be reduced by catalytichydrogenation in a protic solvent such as ethanol or by tin chloride inethyl acetate at reflux temperature. The aniline derivative so obtainedis acylated with (E)-3-ethoxy-2-propenoyl chloride in a solvent such asdichloromethane in the presence of a non-nucleophilic base such aspyridine at a temperature between 0° C. and ambient temperature. Theresultant amide may be cyclized with a concentrated mineral acid suchsulphuric acid at a temperature between 0° C. and ambient temperature.

Compounds of Group G may be prepared by procedures exemplified inReaction Schemes 18 to 19. While the Schemes exemplify compounds of thepresent invention wherein m=n=1, it will be readily apparent to theskilled person that the same procedures may be applied to other ringsizes (i.e. when the sum of m, n, o and p is 3 or more).

Compounds of group G where G is CR⁵ or N; and J is CR⁵ or N may beprepared by the route exemplified in Scheme 18.

An appropriate amino derivative is diazotised under standard conditions(sodium nitrite, hydrochloric acid at or around 0° C.) and treated withpotassium ethyl xanthate in water at or around 80° C. The resultingxanthate may be converted to a thiol using a reducing agent such aslithium aluminium hydride in an aprotic solvent such as diethyl ether ortetrahydrofuran at a temperature between 0° C. and ambient temperature.Subsequent alkylation of the thiol with an appropriate mesylate may bemediated by a base such as potassium carbonate or cesium fluoride in anaprotic solvent such as dimethylformamide. This reaction is performedbetween ambient temperature and 100° C. It will be appreciated by thoseskilled in the art that exo and endo isomers may be obtained and thesecan be separated by crystallisation or chromatography.

A subgroup of compounds of the type G where J=CR⁵, G=N and R3=Cl may beprepared by a route shown in Scheme 19.

An acetylthio compound may be used to displace a halo atom (eg chlorine)from an appropriately substituted ortho-nitrotoluene derivative in areaction mediated by a nucleophilic base such as hydroxide at ambienttemperature. The resultant nitro derivative may be reduced by tinchloride in ethyl acetate at reflux temperature. This is followed byreaction with sodium nitrate in aqueous fluorboric acid at a temperaturebetween 0° C. and ambient temperature. Treatment of the subsequentdiazonium tetrafluoroborate salt with potassium acetate and 18-crown-6in a solvent such as chlororform at ambient temperature gives theappropriate indazole derivatives.

The oxidation of sulfides to sulfones may be achieved by reaction withoxone as shown in Reaction Scheme 20.

To a solution of the azabicylothiophenyl in methanol is added a solutionof Oxone in water. The mixture is stirred at room temperature for about30 minutes and then purified to yield the azabicylosulfonylphenyl.

The conversion of C═O moieties to C═S may be achieved by reaction withLawesson's reagent[2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide)]in a solvent such as toluene at refluxing temperature as shown in Scheme21.

The invention also comprehends derivative compounds (“pro-drugs”) whichare degraded in vivo to yield the species of formula (I). Pro-drugs areusually (but not always) of lower potency at the target receptor thanthe species to which they are degraded. Pro-drugs are particularlyuseful when the desired species has chemical or physical propertieswhich make its administration difficult or inefficient. For example, thedesired species may be only poorly soluble, it may be poorly transportedacross the mucosal epithelium, or it may have an undesirably shortplasma half-life. Further discussion of pro-drugs may be found inStella, V. J. et al., “Prodrugs”, Drug Delivery Systems, 1985, pp.112-176, and Drugs, 1985, 29, pp. 455-473.

Pharmaceutically acceptable salts of the acidic or basic compounds ofthe invention can of course be made by conventional procedures, such asby reacting the free base or acid with at least a stoichiometric amountof the desired salt-forming acid or base.

Pharmaceutically acceptable salts of the acidic compounds of theinvention include salts with inorganic cations such as sodium,potassium, calcium, magnesium, and zinc, and salts with organic bases.Suitable organic bases include N-methyl-D-glucamine, arginine,benzathine, diolamine, olamine, procaine and tromethamine.

Pharmaceutically acceptable salts of the basic compounds of theinvention include salts derived from organic or inorganic acids.Suitable anions include acetate, adipate, besylate, bromide, camsylate,chloride, citrate, edisylate, estolate, fumarate, gluceptate, gluconate,glucuronate, hippurate, hyclate, hydrobromide, hydrochloride. iodide,isethionate, lactate, lactobionate, maleate, mesylate, methylbromide,methylsulfate, napsylate, nitrate, oleate, pamoate, phosphate,polygalacturonate, stearate, succinate, sulfate, sulfosalicylate,tannate, tartrate, terephthalate, tosylate and triethiodide.

Another aspect of the present invention is a pharmaceutical compositioncomprising a compound of formula (I) substantially as describedhereinbefore with a pharmaceutically acceptable diluent or carrier.

It is anticipated that the compounds of the invention can beadministered by oral or parenteral routes, including intravenous,intramuscular, intraperitoneal, subcutaneous, rectal and topicaladministration, and inhalation.

For oral administration, the compounds of the invention will generallybe provided in the form of tablets or capsules or as an aqueous solutionor suspension.

Tablets for oral use may include the active ingredient mixed withpharmaceutically acceptable excipients such as inert diluents,disintegrating agents, binding agents, lubricating agents, sweeteningagents, flavouring agents, colouring agents and preservatives. Suitableinert diluents include sodium and calcium carbonate, sodium and calciumphosphate and lactose. Corn starch and alginic acid are suitabledisintegrating agents. Binding agents may include starch and gelatine.The lubricating agent, if present, will generally be magnesium stearate,stearic acid or talc. If desired, the tablets may be coated with amaterial such as glyceryl monostearate or glyceryl distearate, to delayabsorption in the gastrointestinal tract.

Capsules for oral use include hard gelatine capsules in which the activeingredient is mixed with a solid diluent and soft gelatine capsuleswherein the active ingredient is mixed with water or an oil such aspeanut oil, liquid paraffin or olive oil.

For intramuscular, intraperitoneal, subcutaneous and intravenous use,the compounds of the invention will generally be provided in sterileaqueous solutions or suspensions, buffered to an appropriate pH andisotonicity. Suitable aqueous vehicles include Ringer's solution andisotonic sodium chloride. Aqueous suspensions according to the inventionmay include suspending agents such as cellulose derivatives, sodiumalginate, polyvinyl-pyrrolidone and gum tragacanth, and a wetting agentsuch as lecithin. Suitable preservatives for aqueous suspensions includeethyl and n-propyl p-hydroxybenzoate.

Compounds of the invention have been demonstrated to be active at theneuronal nicotinic, beta 4 receptor. Their functional agonist activityhas been demonstrated in the test described below.

Functional Ca-flux Assay

HEK 293 cell lines expressing different nicotinic receptor β4 subtypesare plated at a density of 50,000 cells/well into poly-D-lysine coated96 well microtitre plates. Twenty-four hours later the cells are washedwith buffer and loaded with Fluo-3 dye (10 M) at room temperature for 1h. The dye is removed and 180 μl of buffer containing atropine at 3 μMadded.

The plates are loaded into a FLIPR (Molecular Devices) and 20 μl ofexperimental compound are added in a concentration gradient across theplate. The stimulation of the nicotinic receptor response to compoundaddition is measured as a rise in fluorescence which correlates to theentry of calcium into the cell. Acetylcholine is added 10 min later toall wells to investigate whether the compounds can block theacetylcholine stimulated nicotine response.

The effects of compounds as nicotinic agonists and antagonists arecalculated using an OMM (Oxford matrix management) curve fit package.

The present invention further provides compounds of formula (I) orcompositions as hereinabove described for use in therapy.

The present invention further provides the use of a compound ashereinbefore described for the manufacture of a medicament for thetreatment of a condition indicating treatment with a beta 4 subtypeselective nicotinic acetylcholine receptor modulator.

The present invention further provides a method of treatment of acondition indicating treatment with a beta 4 subtype selective nicotinicacetylcholine receptor modulator comprising administering an effectiveamount of a compound or a composition as hereinbefore described to apatient in need thereof.

The present invention further provides the use of compounds of formula(I) in the manufacture of a medicament for the treatment of dysfunctionsof the central and autonomic nervous systems. Such dysfunctionsincluded, for example, dementia, cognitive disorders, neurodegenerativedisorders, extrapyramidal disorders, convulsive disorders,cardiovascular disorders, endocrine disorders, eating disorders,affective disorders, and drug abuse.

The present invention further provides a method of treatment ofdysfunctions of the central and autonomic nervous systems comprisingadministering an effective amount of a compound of formula (I) or acomposition as hereinabove described to a patient in need thereof.

The present invention is now further illustrated by means of thefollowing Examples.

EXAMPLE 1 a)Exo-3-(3-methoxyphenylthio)-8-methyl-8-azabicyclo[3.2.1]octane

NaH (60% dispersion in mineral oil, 101 mg, 2.55 mmol) was washed withpetroleum ether 40-60 (2×20 ml) under a flow of nitrogen, then treatedwith THF (˜40 ml) generating a grey cloudy mixture. This mixture wastreated with 3-methoxybenzenethiol (0.30 ml, 2.32 mmol), causing theevolution of gas and the reaction to become clear. After ten minutes thereaction was treated with 8-methyl-8-azabicyclo[3.2.1]oct-3-ylmethanesulphonate (500 mg, 2.32 mmol) as a solution in THF (3×15 ml).The reaction was stirred at reflux under a flow of nitrogen overnightthen concentrated in vacuo to a white sticky solid. This solid wasdissolved in a mixture of H₂O (40 ml) and CHCl₃ (40 ml) then acidifiedusing 2N HCl_((aq)) to pH=2. The organic layer was removed and theaqueous washed with more CHCl₃ (2×40 ml). The aqueous layer was basifiedusing 2N NaOH (pH˜10) then extracted using CHCl₃ (45 ml) and ethylacetate (40 ml). The organic extractions were combined, dried (MgSO₄)and concentrated in vacuo to yield the title compound as a clearcolourless oil (250 mg, 41%).

δ_(H) (300 MHz; CDCl₃) 1.53-1.60 (2H, m, CH₂), 1.77-1.82 (4H, m, 2×CH₂),1.99-2.04 (2H, m, CH₂), 2.27 (3H, s, NCH₃), 3.15-3.17 (2H, m, 2×NCHCH₂),3.28-3.36 (1H, m, HCS), 3.78 (3H, s, Ar—OCH₃), 6.74-6.77 (1H, m, Ar—H),6.93-6.98 (2H, m, 2×Ar—H) and 7.16-7.21 (1H, m, Ar—H); LCMS retentiontime ˜2.62 min, m/z (FIAPOSES) 264.1 [(M+H)⁺, 100%].

By proceeding in a similar manner to Example 1 (a) but using theappropriate mercaptobenzene derivative, there were prepared thefollowing compounds:

b) Exo-3-(4-methoxyphenylthio)-8-methyl-8-azabicyclo[3.2.1]octane

δ_(H) (300 MHz; CDCl₃) 1.50 (2H, m, CH₂), 1.65-1.75 (4H, m, 2×CH₂), 1.98(2H, m, CH₂), 2.22 (3H, s, NCH₃), 3.05 (1H, m, HCS), 3.18 (2H, m,2×NCHCH₂), 3.78 (3H, s, Ar—OCH₃), 6.78 (2H, m, Ar—H); 7.38 (2H, m,Ar—H); m/z (FIAPOSES) 264.1 [(M+H)⁺, 100%].

c) Exo-3-(2-chlorophenylthio)-8-methyl-8-azabicyclo[3.2.1]octane

δ_(H) (300 MHz; DMSO) 1.65 (2H, m, CH₂), 1.75-1.85 (4H, m, 2×CH₂), 1.95(2H, m, CH₂), 2.30 (3H, s, NCH₃), 3.10 (2H, m, 2×NCHCH₂), 3.60 (1H, m,HCS), 7.22 (1H, m, Ar—H), 7.40 (1H, m, Ar—H), 7.50 (2H, m, Ar—H); m/z(FIAPOSES) 268 [(M+H)⁺, 100%].

d) Exo-3-(phenylthio)-8-methyl-8-azabicyclo[3.2.1]octane

δ_(H) (300 MHz; DMSO) 1.63 (2H, m, CH₂), 1.75-1.85 (4H, m, 2×CH₂), 2.00(2H, m, CH₂), 2.30 (3H, s, NCH₃), 3.10 (2H, m, 2×NCHCH₂), 3.30 (1H, m,HCS), 7.22 (3H, m, Ar—H),), 7.38 (2H, m, Ar—H),); m/z (FIAPOSES) 234[(M+H)⁺, 100%].

EXAMPLE 2 Exo-3-(8-methyl-8-azabicyclo[3.2.1]oct-3-ylthio)-benzamide

(i) 3-mercaptobenzamide

To a solution of 3-mercaptobenzoic acid (1.00 g, 6.49 mmol) in DME(ethyleneglycol-dimethylether, ˜15 ml) was added N-methylmorpholine (1.5ml, 13.6 mmol) and iso-butylchloroformate (1.77 ml, 13.6 mmol) under aflow of nitrogen. The clear solution quickly became a cloudy mixture andthe temperature started to rise. After stirring for half an hour thereaction was filtered and then treated with 0.5M NH₃ in dioxane (27 ml,13.5 mmol). The reaction was treated with sodium methoxide in methanol,then quenched with 2N HCl until pH=4 and then concentrated in vacuo to awhite paste. This was partitioned between CHCl₃ and H₂O (3×100 ml) andthe organic layer dried (MgSO₄) and concentrated in vacuo to a whitesolid (1.6 g). This was dissolved in H₂O, basified (2N NaOH, pH=10) andthe aqueous washed with CHCl₃. The aqueous was acidified (2N HCl, pH=2)then extracted with CHCl₃ (2×50 ml). The organic extracts were dried(MgSO₄) then concentrated in vacuo to give 3-mercaptobenzamide as awhite solid (501 mg).

(ii) Exo-3-(8-methyl-8-azabicyclo[3.2.1]oct-3-ylthio)-benzamide

NaH (60% dispersion in mineral oil, 154 mg, 3.84 mmol) was washed withpetroleum ether 40-60 (3×20 ml) then treated with THF (60 ml) under aflow of nitrogen to give a white cloudy mixture. This mixture treatedwith 3-mercaptobenzamide (490 mg, ˜3 mmol) as a solution in THF (3×10ml), then with 8-methyl-8-azabicyclo[3.2.1]oct-3-yl methanesulphonate(490 mg, 2.24 mmol) as a solution in THF (3×5 ml) then slowly warmed toreflux. The reaction was maintained at reflux under a flow of nitrogenfor two days then concentrated in vacuo to a pale yellow solid. This wasdissolved in H₂O (50 ml), acidified (2N HCl, pH=2), washed with CHCl₃(50 ml) and ethyl acetate (50 ml), basified (2N NaOH, pH=10) andextracted with CHCl₃ (50 ml) and ethyl acetate (50 ml). The organicextracts were combined, dried (MgSO₄) and concentrated in vacuo to yieldthe title compound as a colourless crystalline solid (240 mg, 39%), m.p.˜147° C.; δ_(H) (300 MHz; CDCl₃) 1.49-1.61 (2H, m, CH₂), 1.74-1.83 (4H,m, 2×CH₂), 2.00-2.05 (2H, m, CH₂), 2.27 (3H, s, NCH₃), 3.16-3.18 (2H, m,2×NCHCH₂), 3.30-3.37 (1H, m, HCS), 5.96-6.24 (2H, m, CONH₂), 7.28-7.43(2H, m, 2×Ar—H), 7.52-7.55 (1H, m, Ar—H), 7.64-7.66 (1H, m, Ar—H) and7.84-7.85 (1H, m, Ar—H); LCMS retention time ˜1.4 min, m/z (FIAPOSES)277.1 [(M+H)⁺, 100%].

EXAMPLE 3 a)Exo-3-(4-aminophenylthio)-8-methyl-8-azabicyclo[3.2.1]octane

NaH (60% dispersion in mineral oil, 1.59 g, 39.8 mmol) was washed withpetroleum ether 40-60 (2×40 ml) under a flow of nitrogen, then treatedwith THF (˜120 ml) generating a grey cloudy mixture. This mixture wascooled to 0° C. then treated with 4-aminothiophenol (4.77 g, 38.2 mmol)as a solution in THF (4×15 ml), gas could be seen evolving throughoutthe addition. After ten minutes the reaction was treated with8-methyl-8-azabicyclo[3.2.1]oct-3-yl methanesulphonate (6.87 g, 31.8mmol) as a solution in THF (3×20 ml) then slowly warmed to reflux. Thereaction was refluxed for 5 hours then stirred at room temperature fortwo days. The reaction was filtered then concentrated in vacuo to abrown oil (˜9 g) which was added to acidified water (HCl, pH=1,250 ml)then washed with CHCl₃ (2×100 ml). The aqueous layer was basified using2N NaOH (pH˜13) then extracted using CHCl₃ (3×75 ml). The organicextractions were combined, dried (MgSO₄) and concentrated in vacuo to ayellow oil (˜7 g). Flash chromatography (SiO₂ 100 g, gradient elution;CHCl₃:MeOH; 100:0 to 90:10) afforded one major fraction. Evaporationgave the title compound as a pale yellow crystalline solid (3.69 g,47%); (m.p. 79-81° C.); δ_(H) (300 MHz; CDCl₃) 1.48-1.53 (2H, m, CH₂),1.63-1.75 (4H, m, 2×CH₂), 1.94-1.98 (2H, m, CH₂), 2.24 (3H, s, NCH₃),2.98-3.04 (1H, m, HCS), 3.11-3.13 (2H, m, 2×NCHCH₂), 3.74 (2H, br. s,Ar—NH₂), 6.58-6.61 (2H, m, 2×Ar—H) and 7.23-7.26 (2H, m, 2×Ar—H); LCMSretention time ˜1.57 min, m/z (FIAPOSES) 249.1 [(M+H)⁺, 60%] and 125.2(100%).

b) Exo-3-(3-aminophenylthio)-8-methyl-8-azabicyclo[3.2.1]octane

By proceeding in a similar manner to Example 3(a) but using3-aminothiophenol, there was prepared the title compound as a yellowsolid. δ_(H) (300 MHz; CDCl₃) 1.50 (2H, m, CH₂), 1.75-1.85 (4H, m,2×CH₂), 2.20 (2H, m, CH₂), 2.25 (3H, s, NCH₃), 3.10 (2H, m, 2×NCHCH₂),3.25 (1H, m, HCS), 3.60 (2H, br. s, Ar—NH₂), 6.50 (1H, m, Ar—H),), 6.70(1H, m, Ar—H),), 6.77 (1H, m, Ar—H),), 7.05 (1H, m, Ar—H); m/z(FIAPOSES) 249.1 [(M+H)⁺, 100%].

EXAMPLE 4 a)Exo-3-(4-methanesulphonylaminophenylthio)-8-methyl-8-azabicyclo[3.2.1]octane

To a solution ofExo-3-(4-aminophenylthio)-8-methyl-8-azabicyclo[3.2.1]octane (Example3(a), 250 mg, 1.01 mmol) in CHCl₃ (˜75 ml) was added pyridine (79 mg,1.01 mmol) followed by methanesulphonyl chloride (115 mg, 1.01 mmol)both as solutions in CHCl₃ (2×1 ml). The pale yellow solution wasstirred at room temperature under a flow of nitrogen for two days. OnceLCMS showed no more starting material the reaction was quenched with 35%NH₄OH_((aq)) (˜25 ml) then extracted with more CHCl₃ (25 ml). The twoorganic extracts were combined and washed with NH₄OH_((aq)) then dried(MgSO₄) and concentrated in vacuo to a yellow oil. Excess pyridine whichwas removed under vacuum, the remaining oil was purified usingpreparative LCMS, yielding the title compound as a thick sticky paste(117 mg, 36%); δ_(H) (300 MHz; CDCl₃) 1.88-1.93 (4H, m, 2×CH₂),2.22-2.30 (4H, m, 2×CH₂), 2.60 (3H, s, ⁺NCH₃), 3.00 (3H, s, SO₂CH₃),3.11-3.18 (1H, m, HCS), 3.76 (2H, br. s, 2×⁺NCHCH₂), 4.5-5.5 (1H, br. s,Ar—NH), 7.20-7.23 (2H, m, 2×Ar—H), 7.40-7.43 (2H, m, 2×Ar—H) and 8.40(1H, s, HCO₂ ⁻); LCMS retention time ˜2.02 min, m/z (FIAPOSES) 327.1[(M+H)⁺, 100%].

b) Exo-3-(4-acetylaminophenylthio)-8-methyl-8-azabicyclo[3.2.1]octane.

By proceeding in a manner similar to example 4(a) but using aceticanhydride in place of methanesulphonyl chloride there was prepared thetitle compound as a pale yellow solid. δ_(H)(300 MHz; CDCl₃) 1.90-2.00(4H, m, 2×CH₂), 2.05-2.20 (4H, m, 2×CH₂), 2.50 (3H, s, COCH₃), 2.60 (3H,s, NCH₃), 3.50 (1H, m, HCS), 3.75 (2H, br. s, 2×NCHCH₂), 7.40 (2H, m,2×Ar—H), 7.65 (2H, m, 2×Ar—H); m/z (FIAPOSES) 291 [(M+H)⁺, 100%].

c) Exo-3-(3-acetylaminophenylthio)-8-methyl-8-azabicyclo[3.2.1]octane

By proceeding in a manner similar to example 4(a) but using aceticanhydride in place of methanesulphonyl chloride andexo-3-(3-aminophenylthio)-8-methyl-8-azabicyclo[3.2.1]octane [Example3(b)] there was prepared the title compound as a pale yellow solid.δ_(H) (300 MHz; CDCl₃) 1.90-2.10 (4H, m, 2×CH₂), 2.15-2.20 (4H, m,2×CH₂), 2.60 (3H, s, COCH₃), 2.65 (3H, s, NCH₃), 3.38 (2H, br. s,2×NCHCH₂), 3.60 (1H, m, HCS), 7.10 (1H, m, Ar—H),), 7.23 (1H, m,Ar—H),), 7.42 (1H, m, Ar—H),), 7.81 (1H, m, Ar—H); m/z (FIAPOSES) 291[(M+H)⁺, 100%].

EXAMPLE 5 Exo-4-(8-methyl-8-azabicyclo[3.2.1]oct-3-ylthio)-benzamide

(i) 4-mercaptobenzamide

To a stirred solution of 4-mercaptobenzoic acid (1.00 g, 6.49 mmol) andN-methylmorpholine (0.78 ml, 7.14 mmol) in ethyleneglycol-dimethylether(20 ml) was added iso-butylchloroformate (0.92 ml, 7.14 mmol). Thereaction was stirred at ambient temperature overnight and filtered to aclear pale yellow solution which was treated with excess ammonia as asolution in dioxane (0.5M, ˜15 ml). This solution was stirred for twohours at room temperature, and concentrated in vacuo to a white solid.The solid was dissolved in a mixture of H₂O (10 ml) and CHCl₃ (30 ml),the aqueous was basified using 2N NaOH_((aq)) and the organic layerseparated and dried (MgSO₄) before being concentrated in vacuo to awhite solid (679 mg). The solid was treated with a solution of sodiummethoxide in methanol (10 ml) and when TLC showed no more startingmaterial, the reaction was acidified using 2N HCl_((aq)) to pH=4, thenconcentrated in vacuo. The residue was treated with water and extractedwith CHCl₃, then concentrated in vacuo to give the title compound as anoff white solid (376 mg).

(ii) Exo-4-(8-methyl-8-azabicyclo[3.2.1]oct-3-ylthio)-benzamide

NaH (60% dispersion in mineral oil, 96 mg, 2.40 mmol) was washed withpetroleum ether 40-60 (3×20 ml) under a flow of nitrogen, then treatedwith THF (˜40 ml) generating a grey cloudy mixture. This mixture treatedwith a solution of 4-mercaptobenzamide (˜376 mg, ˜2 mmol) in THF (3×10ml) then 8-methyl-8-azabicyclo[3.2.1]oct-3-yl methanesulphonate (432 mg,2.0 mmol) as a solution in THF (3×5 ml). The reaction was stirred atreflux under a flow of nitrogen overnight then concentrated in vacuo toa fine yellow solid. The solid was treated with a mixture of H₂O (20 ml)and CHCl₃ (20 ml) then acidified using 2N HCl_((aq)) to pH=2. Theorganic layer was removed and the aqueous washed with ethyl acetate (20ml). The aqueous layer was basified using 2N NaOH (pH˜10) then extractedusing CHCl₃ (20 ml) and ethyl acetate (20 ml). The combined organicextractions were dried (MgSO₄) and concentrated in vacuo to an orangeoil (392 mg). The oil was purified by preparative LCMS, yielding thetitle compound as a colourless oil (148 mg); δ_(H) (300 MHz; CDCl₃)1.85-1.97 (4H, m, 2×CH₂), 2.15-2.59 (4H, m, 2×CH₂), 2.59 (3H, s, ⁺NCH₃),3.33-3.45 (1H, m, HCS), 3.66 (2H, br. s, 2×⁺NCHCH₂), 7.43-7.46 (2H, m,2×Ar—H), 7.74-7.76 (2H, m, 2×Ar—H) and 8.39 (1H, s, HCO₂—); LCMSretention time ˜1.55 min, m/z (FIAPOSES) 277.1 [(M+H)⁺, 100%].

EXAMPLE 6 Exo-N-methyl4-(8-methyl-8-azabicyclo[3.2.1]oct-3-ylthio)-benzamide

(i) N-Methyl 3-mercaptobenzamide

To a solution of 3-mercaptobenzoic acid (1.00 g, 6.49 mmol) inethyleneglycol-dimethylether (10 ml) was added N-methylmorpholine (1.5ml, 13.6 mmol) and iso-butylchloroformate (1.77 ml, 13.6 mmol) under aflow of nitrogen at 0° C. The clear solution quickly became a thickpaste. After stirring for one hour the reaction was filtered and thentreated with 2M methylamine in THF (7 ml, 14 mmol). The reaction wasstirred for two days at room temperature and then treated with 0.5Msodium methoxide in methanol (14 ml). The reaction was stirred for threehours, then quenched with 2N HCl until pH=4 and concentrated in vacuo toa semi solid. This was dissolved in H₂O (50 ml), basified (2N NaOH,pH=10), washed with CHCl₃ (2×50 ml), acidified (2N HCl, pH=2) thenextracted with CHCl₃ (50 ml) and ethyl acetate (50 ml). The organicextracts were combined, dried (MgSO₄) then concentrated in vacuo to acolourless oil (570 mg).

(ii) Exo-N-methyl 4-(8-methyl-8-azabicyclo[3.2.1]oct-3-ylthio)-benzamide

NaH (60% dispersion in mineral oil, 179 mg, 4.48 mmol) was washed withpetroleum ether 40-60 (2×20 ml) then treated with THF (40 ml) under aflow of nitrogen to give a white cloudy mixture. This mixture treatedwith N-methyl 3-mercaptobenzamide (570 mg, ˜3.7 mmol) as a solution inTHF (2×10 ml), then with 8-methyl-8-azabicyclo[3.2.1]oct-3-ylmethanesulphonate (572 mg, 2.61 mmol) as a solution in THF (3×5 ml). Thereaction was heated at reflux under a flow of nitrogen overnight thenconcentrated in vacuo to a pale yellow solid. This was dissolved in H₂O(50 ml), acidified (2N HCl, pH=2) and washed with CHCl₃ (50 ml) andethyl acetate (50 ml). The aqueous was basified (2N NaOH, pH=10) andextracted with CHCl₃ (50 ml) and ethyl acetate (50 ml). The organicextracts were combined, dried (MgSO₄) and concentrated in vacuo to apale yellow oil (402 mg). Purification by preparative LCMS yielded thetitle compound as a colourless crystalline solid (300 mg, 40%); m.p.˜87-89° C.; δ_(H) (300 MHz; CDCl₃) 1.82-1.99 (4H, m, 2×CH₂), 2.17-2.36(4H, m, 2×CH₂), 2.60 (3H, s, ⁺NCH₃), 2.99-3.01 (3H, d, J=4.5 Hz,CONCH₃), 3.20-3.32 (1H, m, HCS), 3.68 (2H, br. s, 2×NCHCH₂), 7.33-7.38(1H, m, Ar—H), 7.49-7.52 (1H, m, Ar—H), 7.70-7.73 (1H, m, Ar—H),7.79-7.80 (1H, m, Ar—H) and 8.70 (1H, s, HCO2⁻); LCMS retention time˜2.0 min, m/z (FIAPOSES) 291.1 [(M+H)⁺, 100%].

EXAMPLE 7 Exo-3-(8-methyl-8-azabicyclo[3.2.1]oct-3-ylthio)-benzoic acid

NaH (60% dispersion in mineral oil, 2.18 g, 54.5 mmol) treated with THF(˜210 ml) and DMF (70 ml), under a flow of nitrogen to give a whitecloudy mixture. This mixture treated with 3-mercapto-benzoic acid (4.00g, 25.9 mmol) as a solution in THF (6×5 ml) dropwise over 20 minutes,gas could be seen evolving throughout the addition. Large amounts of asticky solid began to form in the solution so more DMF (70 ml) was addedto help solvation. After 30 minutes the reaction was treated with8-methyl-8-azabicyclo[3.2.1]oct-3-yl methanesulphonate (5.6 g, 25.9mmol) as a solution in THF (2×10 ml) then slowly warmed to reflux for 4hours. The reaction was stirred at room temperature overnight to give ayellow cloudy mixture which was concentrated in vacuo to a thick yellowoil, which could be purified by recrystallizing from 10:1H₂O:CH₃CN toyield the title compound as a crystalline solid (1.65 g, 23%); (m.p.249-251° C.); δ_(H) (300 MHz; D₂O) 1.81-2.21 (8H, m, 4×CH₂), 2.64 (3H,s, ⁺NCH₃), 3.41-3.54 (1H, m, HCS), 3.80 (2H br. s, 2×⁺NCHCH₂), 7.32-7.41(1H, m, Ar—H), 7.47-7.54 (1H, m, Ar—H), 7.74-7.76 (1H, m, Ar—H) and 7.87(1H, br. s, Ar—H); δ_(H) (300 MHz; methanol d4) 2.01-2.18 (6H, m,3×CH₂), 2.29-2.32 (2H, m, CH₂), 2.75 (3H, s, ⁺NCH₃), 3.57-3.60 (1H, m,HCS), 3.88 (2H br. s, 2×⁺NCHCH₂), 7.35-7.54 (1H, m, Ar—H), 7.55-7.57(1H, m, Ar—H), 7.86-7.89 (1H, m, Ar—H) and 8.04-8.05 (1H, m, Ar—H); LCMSretention time ˜1.9 min, m/z (FIAPOSES) 278.1 [(M+H)⁺, 100%].

EXAMPLE 8 Exo-3-(8-methyl-8-azabicyclo[3.2.1]oct-3-ylthio)-benzylalcohol

A solution of exo-3-(8-methyl-8-azabicyclo[3.2.1]oct-3-ylthio)-benzoicacid (Example 7, 230 mg) in chloroform (50 ml) was treated withtriethylamine (90 mg) and isobutyl chloroformate (119 mg). Afterstirring at ambient temperature for 2 hours, the reaction mixture wasconcentrated in vacuo. The residue was dissolved in ethylene glycoldimethyl ether (40 ml) and treated dropwise with a solution of sodiumborohydride (34 mg) in water (2 ml) over 30 minutes. After stirring afurther 1 hour at ambient temperature, the reaction mixture waspartitioned between ethyl acetate (30 ml) and water (10 ml). The organiclayer was dried over magnesium sulphate and concentrated to dryness. Theresidue was purified by preparative HPLC to give the title compound (60mg) as a white solid.

EXAMPLE 93-Bromo-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3(exo)-ylsulfanyl)-phenol

(i) 3-Bromo-4-thiocyanato-phenol

To an ice-cooled suspension of Pb(SCN)₂ (1.81 g, 5.6 mmol) in drymethylene chloride (27 mL) PhICl₂ (0.97 g, 3.54 mmol, (preparedaccording to D. Koyuncu et al., J. Chem. Res. (S) 1990, 21) was addedand the resulting mixture was stirred for 30 min at 0° C. undernitrogen. A solution of 3-bromophenol (250 mg, 1.44 mmol) in drymethylene chloride (3 mL) was added, the mixture was stirred for 2 h at0° C. and filtered in cold through a celite® pad washing extensivelywith ethyl acetate. After addition of silicagel to the filtrate andevaporation of solvents, the mixture was purified by flashchromatography (30% ethyl acetate/hexanes) to afford 0.32 g (47%) of thetitle compound as a brown solid.

m.p. 91-92° C.

(ii) 3-Bromo-4-mercaptophenol

To a hot (85° C.) solution of 3-bromo-4-thiocyanato-phenol (315 mg, 1.37mmol) in absolute ethanol (10 mL) under nitrogen, sodium sulfidenonahydrate (403 mg, 2.05 mmol) was added. The resulting mixture wasstirred at 85° C. for 20 min. More sodium sulfide nonahydrate (230 mg)was added and heating was continued for 15 min. The mixture was cooleddown, made acidic with 5N acetic acid (10 mL) and extracted withmethylene chloride (×1). The organic layer was washed once with water,dried and concentrated in vacuo to give the title compound as a yellowsolid (259 mg, 92%) which was quickly submitted to the next reactionwithout further treatment.

EIMS M−1: 203.

(iii) 3-Bromo-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3(exo)-ylsulfanyl)-phenol.

To a solution of 3-bromo-4-mercaptophenol (259 mg, 1.3 mmol) andmethanesulfonic acid 8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl ester (240mg, 1.1 mmol) in dry dimethylformamide (10 mL) under nitrogen, potassiumcarbonate (407 mg, 2.75 mmol) was added. The resulting mixture wasvigorously stirred at room temperature for 18 h under nitrogen and 10%hydrochloric acid was added. The mixture was washed with ethyl acetate(×3), the aqueous layer made basic (pH=8) with solid sodium bicarbonateand extracted with ethyl acetate (×4). The combined organic phase wasconcentrated in vacuo and purified by flash chromatography (10%Methanol/1% ammonia/methylene chloride) to give the title compound, 170mg (47%).

EIMS M+1: 328.

¹H NMR (200 MHz, CD₃OD) δ 7.37 (d, J=8.6 Hz, 1H), 7.07 (d, J=2.7 Hz,1H), 6.69 (dd, J=8.4, 2.7 Hz, 1H), 3.19 (br m, 3H), 2.25 (s, 3H), 2.05(m, 2H), 1.77-1.71 (m, 4H), 1.60 (d, J=8.0 Hz, 2H).

¹³C NMR (300 MHz, CD₃OD) δ 160.9, 139.0, 131.9, 124.4, 122.0, 116.9,63.3, 40.2, 39.8, 39.2, 27.1.

EXAMPLE 105-Hydroxy-2-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-benzonitrile

3-Bromo-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3(exo)-ylsulfanyl)-phenol(35 mg, 0.1 mmol), zinc cyanide (23 mg, 0.2 mmol) and DPPF (28 mg, 0.05mmol) were dissolved in degassed and dry DMF (0.2 mL). To the abovemixture, Pd₂(dba)₃ (18 mg, 0.02 mmol) was added and the resultingmixture was stirred at 120° C. for 6 h, cooled down, diluted with ethylacetate and filtered through a celite® pad. The filtrate was washed oncewith a saturated sodium bicarbonate solution and extracted with 10%hydrochloric acid (×2). The aqueous phase was concentrated in vacuo andpurified by SCX to afford 5.5 mg (20%) of the title compound.

EIMS M+1: 275.

¹H NMR (200 MHz, CD₃OD) δ 7.45 (d, J=8.3 Hz, 1H), 7.05 (d, J=2.7 Hz,1H), 6.96 (dd, J=58.6, 2.7 Hz, 1H), 3.30 (br m, 3H), 2.30 (s, 3H), 2.08(m, 2H), 1.83-1.78 (m, 4H), 1.67 (d, J=8.3 Hz, 2H).

¹³C NMR (300 MHz, CD₃OD) δ 160.8, 138.4, 124.0, 121.6, 120.9, 119.7,117.9, 62.1, 39.5, 38.6, 37.6, 25.6.

EXAMPLE 11 4-(8-methyl-8-aza-bicyclo[3.2.1]oct-6-en-3(exo)-ylsulfanyl)-phenol

(i) Methanesulfonic acid8-methyl-8-aza-bicyclo[3.2.1]oct-6-en-3(endo)-yl ester.

To a solution of 8-methyl-8-aza-bicyclo[3.2.1]oct-6-en-3-olhydrochloride (from E-Merck, 3.0 g, 17.08 mmol) in CH₂Cl₂ (30 mL)pyridine (2.7 mL, 2.64 g, 34.16 mmol) and methanesulfonyl chloride (1.6mL, 2.37 g, 20.50 mmol) were added and the mixture was stirred at 23° C.for 72 h. Then the reaction was diluted with CH₂Cl₂ and Washedsuccessively with aq NH₄OH 32% and brine. The combined aqueous phase wasextracted with CH₂Cl₂ and the organic phase was dried and concentratedin vacuo to afford the mesylate as a pale yellow solid (2.2 g, 59%) thatwas used without further purification.

m. p. 64-65° C.

¹H NMR (200 MHz, CDCl₃) δ 6.02 (br s, 2H), 4.88 (t, J=5.8 Hz, 1H), 3.39(br s, 2H), 2.9 (s, 3H), 2.36-2.26 (m, 2H), 2.26 (s, 3H), 1.98-1.90 (m,2H).

(ii) 4-(8-methyl-8-aza-bicyclo[3.2.1]oct-6-en-3(exo)-ylsulfanyl)-phenol.

To a mixture of the compound from step A (500 mg, 2.3 mmol) and4-mercaptophenol (380 mg, 3.0 mmol) in dry DMF (15 mL), potassiumcarbonate (920 mg, 6.22 mmol) was added. The resulting mixture wasvigorously stirred at room temperature for 16 h. The mixture was dilutedwith ethyl acetate and extracted with 10% hydrochloric acid (×2). Thecombined aqueous phase was neutralised with sodium carbonate, extractedwith ethyl acetate (×6), dried (Na₂SO₄) and evaporated. The crude waspurified by flash chromatography (5% Methanol/1% ammonia/methylenechloride) to give the title compound, 120 mg (21%) as a white solid.

EIMS M+1: 248.

¹H NMR (200 MHz, CD₃OD) δ 7.23 (d, J=8.6 Hz, 2H), 6.70 (d, J=8.6 Hz,2H), 5.89 (s, 2H), 3.47 (br s, 2H), 2.93 (m, 1H), 2.15 (s, 3H), 1.73 (d,J=3.0 Hz, 2H), 1.68 (t, J=2.9 Hz, 2H).

¹³C NMR (300 MHz, CD₃OD) δ 159.9, 138.2, 131.0, 124.6, 117.7, 69.1,41.6, 41.5, 34.5.

EXAMPLE 12 4-(8-methyl-8-aza-bicyclo[3.2.1]oct-6-en-3(endo)-ylsulfanyl)-phenol

To a mixture of methanesulfonic acid8-methyl-8-aza-bicyclo[3.2.1]oct-6-en-3(endo)-yl ester (326 mg, 1.5mmol) and 4-mercaptophenol (210 mg, 1.65 mmol) in acetone (10 mL), K₂CO₃(1.33 g, 9.0 mmol) was added. The resulting mixture was stirred at 65°C. for 16 h. The mixture was diluted with brine and extracted withCH₂Cl₂ (×5), dried (Na₂SO₄) and evaporated. The crude was purified byflash chromatography (8% Methanol/1% ammonia/methylene chloride) to givethe title compound, 57 mg (15%) as a white solid.

EIMS M+1: 248.

¹H NMR (200 MHz, CD₃OD) δ 7.16 (d, J=8.6 Hz, 2H), 6.69 (d, J=8.8 Hz,2H), 6.05 (s, 2H), 3.48 (br s, 2H), 3.10 (t, J=7.2 Hz, 1H), 2.36 (dd,J=7.3, 3.5 Hz, 1H), 2.29 (dd, J=7.4, 3.5 Hz, 1H), 2.26 (s, 3H), 1.91 (d,J=14.2 Hz, 2H).

¹³C NMR (300 MHz, CD₃OD) δ 159.3, 136.0, 133.9, 130.1, 117.8, 68.4,44.1, 42.1, 36.4.

EXAMPLE 13 3-Chloro-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-6-en-3(exo)-ylsulfanyl)-phenol, trifluoroacetate salt

To a mixture of methanesulfonic acid8-methyl-8-aza-bicyclo[3.2.1]oct-6-en-3(endo)-yl ester (366 mg, 1.69mmol) and 3-chloro-4-mercaptophenol (379 mg, 2.36 mmol) in dry DMF (11mL), K₂CO₃ (675 mg, 4.6 mmol) was added. The resulting mixture wasstirred at room temperature for 16 h. The mixture was diluted with ethylacetate and extracted with 10% hydrochloric acid (×2). The combinedaqueous phase was neutralised with sodium carbonate, extracted withethyl acetate (×6), dried (Na₂SO₄) and evaporated. The crude waspurified by flash chromatography (5% Methanol/1% ammonia/methylenechloride) and reverse phase HPLC to give the title compound as a whitesolid.

EIMS M+1: 282.

¹H NMR (200 MHz, CDCl₃) δ 7.42 (d, J=8.6 Hz, 1H), 6.92 (dd, J=2.4 Hz,1H), 6.72 (dd, J=8.6, 2.4 Hz, 1H), 6.13 (d, J=0.8 Hz, 2H), 4.31 (br s,2H), 3.28 (m, 1H), 2.77 (s, 3H), 2.17-1.91 (m, 4H).

¹³C NMR (300 MHz, CDCl₃) δ 160.8, 141.0, 139.6, 128.3, 121.0, 118.2,116.0, 69.9, 39.2, 38.1, 31.9.

EXAMPLE 142-Methyl-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3(exo)-ylsulfanyl)-phenol,trifluoroacetate salt

(i) 2-Methyl-4-thiocyanato-phenol

To an ice-cooled suspension of Pb(SCN)₂ (485 mg, 1.5 mmol) in drymethylene chloride (10 mL), PhICl₂ (330 mg, 1.2 mmol) was added and theresulting mixture was stirred for 25 min at 0° C. under nitrogen. Asolution of o-cresol (108 mg, 1 mmol) in dry methylene chloride (2 mL)was added dropwise. The mixture was stirred for 1 h at 0° C. andfiltered through a celite® pad washing extensively with methylenechloride. After addition of silicagel to the filtrate and evaporation ofsolvents, the mixture was purified by flash chromatography (10% ethylacetate/hexane) to afford 164 mg (99%) of the title compound as a whitesolid.

m.p. 64-68° C.

EIMS M+1: 166.

IR (cm⁻¹): 3406, 1637, 1495, 1276, 1180, 814.

¹H NMR δ (ppm) (200 MHz, CDCl₃): 7.31 (d, J=2.4 Hz, 1H), 7.23 (dd, J=8.6Hz, 2.4 Hz, 1H), 6.79 (d, J=8.6 Hz, 1H), 2.21 (s, 3H).

¹³C NMR δ (ppm) (200 MHz, CDCl₃): 155.6 (C), 134.1 (CH), 130.5 (CH),126.3 (C), 115.7 (CH), 111.9 (C), 111.0 (C), 14.8 (CH₃).

(ii)2-Methyl-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3(exo)-ylsulfanyl)-phenol,trifluoroacetate salt

To a solution of 2-methyl-4-thiocyanato-phenol (160 mg, 0.97 mmol) inabsolute ethanol (8 mL) under nitrogen, sodium sulfide nonahydrate (298mg, 1.16 mmol) was added. The resulting mixture was stirred at 85° C.for 30 min and a solution of methanesulfonic acid8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl ester (254 mg, 1.16 mmol) inabsolute ethanol (4 mL) was added dropwise at 85° C. The mixture wasstirred for 2 h. The solvent was removed in vacuo and residue wassubmitted to a SCX collecting a mixture exo/endo. This mixture waspurified by reverse phase HPLC to obtain the title compound (20 mg, 5%).

EIMS M+1: 264.

¹H NMR δ (ppm) (200 MHz, CDCl₃): 7.20 (d, J=2 Hz, H-7, 1H), 7.12 (dd,J=8 Hz, 2 Hz, H-11, 1H), 6.74 (d, J=8 Hz, H-10, 1H), 4.87 (br s, ArOH,1H), 3.82 (br, H-2,2H), 3.02 (m, H-5, 1H), 2.66 (d, J=4.8 Hz, CH₃ —N⁺H,3H), 2.23 (m, H-3, 4H), 2.20 (s, CH₃Ar, 1H), 1.97 (m, H-4, 2H), 1.93 (m,H-4, 2H).

¹³C NMR δ (ppm) (200 MHz, CDCl₃): 156.2 (C, C-9), 138.7 (CH, C-7), 135.0(CH, C-11), 125.8 (C, C-8), 120.6 (C, C-6), 116.1 (CH, C-10), 63.9(2CH,C-2), 39.2 (CH₃, CH₃ —N⁺H, C-1), 36.9 (2CH₂, C-4), 36.6 (CH, C-5), 24.9(2CH₂, C-3), 16.3 (CH₃, CH₃Ar).

EXAMPLE 155-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-biphenyl-2-ol,trifluoroacetate salt

(i) 5-Thiocyanato-biphenyl-2-ol

To an ice-cooled suspension of Pb(SCN)₂ (569 mg, 1.76 mmol) in drymethylene chloride (10 mL), PhICl₂ (390 mg, 1.42 mmol) was added and theresulting mixture was stirred for 30 min at 0° C. under nitrogen. Asolution of 2-phenyl-phenol (200 mg, 1.18 mmol) in dry methylenechloride (5 mL) was added dropwise. The mixture was stirred for 18 h atroom temperature and filtered through a celite® pad washing extensivelywith methylene chloride. After addition of silica gel to the filtrateand evaporation of solvents, the mixture was purified by flashchromatography (10% ethyl acetate/hexane) to afford 171 mg (64%) of thetitle compound.

EIMS M+1: 228.

IR (cm⁻¹): 3405, 1638, 1446, 1280, 1073.

¹H NMR δ (ppm) (200 MHz, CDCl₃): 7.44-7.35 (m, 7H), 6.98 (d, J=8.6 Hz,1H).

¹³C NMR δ (ppm) (200 MHz, CDCl₃): 155.5 (C), 136.0 (C), 134.9 (CH),133.4 (CH), 131.1 (C), 129.6 (2CH₂), 129.5 (2CH₂), 128.9 (CH), 118.5(CH), 113.8 (C), 112.5 (C).

(ii) 5-Mercapto-biphenyl-2-ol

To a solution of 5-thiocyanato-biphenyl-2-ol (160 mg, 0.97 mmol) inabsolute ethanol (8 mL) under nitrogen, sodium sulfide nonahydrate (298mg, 1.16 mmol) was added. The resulting mixture was stirred at 85° C.for 20 min. The mixture was cooled down, made acidic with 10% aqueousHCl and extracted with ethyl acetate (×2). The combined organic layerswere dried on MgSO₄ and concentrated in vacuo to give the title compoundas a yellow solid (105 mg, 95%) which was quickly submitted to the nextreaction without further purification.

EIMS M−1: 201.

(iii) 5-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-biphenyl-2-ol,trifluoroacetate salt.

To a solution of 5-mercapto-biphenyl-2-ol (105 mg, 0.52 mmol) inanhydrous acetone (3 ml), potassium carbonate (720 mg, 5.2 mmol) wasadded at room temperature. The mixture was stirred under nitrogenatmosphere and methanesulfonic acid8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl ester (103 mg, 0.47 mmol) inacetone (2 ml) was added dropwise. The resulting mixture was vigorouslystirred at 70° C. for 18 h under nitrogen and was filtered and thesolvent was removed in vacuo. The resulting residue was purified byreverse phase HPLC to afford the title compound (38 mg, 17%).

EIMS M+1: 264.

¹H NMR δ (ppm) (500 MHz, DMSO): 9.94 (br s, OH, 1H), 9.31 (br s, NH,1H), 7.55 (d, J=7.3 Hz, H-13, 2H), 7.41 (t, J=7.3 Hz, H-14, 2H), 7.33(m, H-7, 1H), 7.32 (m, H-15, 1H), 7.28 (dd, J=8.5, 2.6 Hz, H-11, 1H),6.96 (d, J=8.5 Hz, H-10, 1H), 3.82 (br s, H-2, 2H), 3.35 (m, H-5, 1H),2.59 (d, J=5.1 Hz, CH₃—N+H, 3H), 2.14 (m, H-3, 2H), 1.97 (m, H-4, 2H),1.86 (t, J=12.3 Hz, H-4, 2H), 1.92 (m, H-3, 2H).

¹³C NMR δ (ppm) (125 MHz, DMSO): 154.9 (C, C-9), 137.6 (C, C-12), 136.9(CH, C-7), 135.2 (CH, C-11), 129.0 (2CH, C-13), 128.4 (C, C-8), 127.9(2CH, C-14), 126.8 (CH, C-15), 116.7 (CH, C-10), 63.1 (2CH, C-2), 38.0(CH₃, CH₃ —N⁺H, C-1), 36.2 (2CH₂, C-4), 35.3 (CH, C-5), 23.5 (2CH₂,C-3).

EXAMPLE 16 2,5-Dichloro-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3(exo)-ylsulfanyl)-phenol

(i) 2,5-Dichloro-4-hydroxy-benzenesulfonyl chloride

2,5-Dichlorophenol (1.00 g, 6.17 mmol) was gradually added tochorosulfonic acid (2 mL, 30.85 mmol) at 0° C. Then it was heated at 80°C. for 1 hour. Then it was cooled at room temperature and poured ontocrushed ice. Then ethyl acetate was added. The layers were separated andthe aqueous phase was extracted with ethyl acetate. The combined organicphase was dried over MgSO₄, filtered and concentrated in vacuo to give1.30 g (81%) of the title compound as a white solid, which was used inthe next reaction without further purification.

EIMS M−1: 259.

(ii) 2,5-Dichloro-4-mercaptophenol

To a mixture of 2,5-dichloro-4-hydroxy-benzenesulfonyl chloride (1.28 g,4.92 mmol) and a solution of 25% of H₂SO₄ (17 mL), Zinc dust (1.64 g,24.56 mmol) was added slowly at room temperature. The reaction mixturewas allowed to stir at 120° C. overnight. The mixture was then cooled atroom temperature and toluene was added. The layers were separated andthe aqueous phase was dried over, MgSO₄ filtered and concentrated invacuo to give 514 mg (54%) of the title compound as a white solid, whichwas used in the next reaction without further purification.

EIMS: 193.

(iii)2,5-Dichloro-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-6-en-3(exo)-ylsulfanyl)-phenol.

To a solution of 2,5-dichloro-4-mercaptophenol (487 mg, 2.51 mmol) inacetone (5 mL), K₂CO₃ (3.20 g, 22.8 mmol) and a solution ofmethanesulfonic acid 8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl ester (500mg, 2.28 mmol) in acetone (5 mL) were added at room temperature. Theresulting mixture was allowed to stir under reflux overnight. Themixture was concentrated in vacuo. The crude was purified first byChromatography (Strong Cation Exchange, 2M ammonia in methyl alcohol)and then by reverse phase HPLC to afford the title compound (78 mg, 8%)as a white solid.

m. p. 193-194° C.

EIMS M+1: 318.

¹H NMR δ (ppm) (200 MHz, MeOH-d4): 7.59 (s, 1H), 7.06 (s, 1H), 3.88 (s,2H), 3.49 (m, 1H), 2.72 (s, 3H), 2.31-1.88 (m, 8H).

EXAMPLE 173,5-Dichloro-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-(exo)-ylsulfanyl)-phenol

(i) 3,5-Dichloro-4-hydroxy-benzenesulfonyl chloride

3,5-Dichlorophenol (2.43 g, 14.9 mmol) was gradually added tochorosulfonic acid (4.9 mL, 74.6 mmol) at 0° C. Then it was heated at80° C. for 1 hour. Then it was cooled at room temperature and pouredonto crushed ice. The resulting white solid was filtered and washed withcool water. The solid was dissolved in EtOAc and dried over MgSO₄,filtered and concentrated in vacuo (CIV) to give 2.24 g (58%) of thetitle compound as a white solid, which was used in the next reactionwithout further purification.

Ion Electrospray Mass Spectrum M−1: 259.

(ii) Acetic acid 2,6-dichloro-4-thiocyanato-phenyl ester

To compound from step (i) (1.00 g, 3.85 mmol), acetic acid (16 mL),acetic acid (16 mL), acetic anhydride (5.5 mL) and sodium acetate (1.60g, 19.5 mmol) were added at room temperature. After stirring for 5 min.,zinc dust (1.60 g) was added. The mixture was refluxed for 2 hours. Thenit was cooled and the resulting solid was filtered, and the solvent wasremoved under vacuo. The residue was triturated with water, filtered andwashed with water. The resulting solid was dissolved with CH₂Cl₂, driedover MgSO₄, filtered and CIV, affording 700 mg (65%) of the finalcompound as a white solid.

(iii) Acetic acid 2,6-dichloro-4-mercaptophenyl ester

To a suspension of compound from step (ii) (472 mg, 1.69 mmol) in MeOH(17 mL), a solution of sodium thiomethoxide (130 mg, 1.86 mmol) in MeOH(4 mL) was added at room temperature. The reaction mixture was allowedto stir at rt, under nitrogen atmosphere overnight. Then it wasconcentrated in vacuo and a 0.1M solution of HCl (30 mL) and CH₂Cl₂ wereadded. The layers were separated and the aqueous phase was extractedwith CH₂Cl₂. The combined organic phase was dried over MgSO₄, filteredand CIV to afford 315 mg (79%) of the final compound as a white solid.

Ion Electrospray Mass Spectrum M+1: 237.

(iv)3,5-Dichloro-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-6-en-3-(exo)-ylsulfanyl)-phenol.

To a suspension of NaH (35 mg, 1.40 mmol) in dry THF (10 mL), undernitrogen atmosphere, a solution of compound from step (iii) (300 mg,1.27 mmol) in dry THF (5 mL) was added at room temperature. The mixturewas allowed to stir at this temperature for 15 min. Then a solution ofmethanesulfonic acid 8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl ester (252mg, 1.15 mmol) in dry THF (5 mL) was added. The reaction mixture wasstirred under reflux for 2 days. Then it was cooled and concentrated invacuo. The crude was purified first by chromatography (Strong CationExchange, 2M ammonia in methyl alcohol) giving an exo/endo mixture. Thismixture was purified by reverse phase HPLC to obtain the title compound(5.6 mg, 1%) as a white solid.

Ion Electrospray Mass Spectrum M+1: 318

¹H NMR δ (ppm) (200 MHz, MeOH-d4): 7.45 (s, 2H), 3.87 (br s, 2H),3.49-3.38 (m, 1H), 2.72 (s, 3H), 2.31-1.83 (m, 8H).

EXAMPLE 182-Bromo-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-(exo)-ylsulfanyl)-phenol

(i) 2-bromo-4-thiocyanatophenol

To a suspension of lead thiocyanate (6.49 g, 20.05 mmol) in CH₂Cl₂ (125mL) under nitrogen at 0° C. PhICl₂ (4.41 g, 16.05 mmol) was added in oneportion. After 20 min at 0° C. a solution of 2-bromophenol (2.31 g, 1.55mL, 13.37 mmol) in CH₂Cl₂ (10 mL) was added. After stirring the mixturefor 45 min at 0° C. the salts were filtered and the solvent evaporated.The crude mixture was purified by silica gel flash chromatography(hexane-EtOAc 5:1-+2:1) to yield 1 (2-bromo-4-thiocyanatophenol) (1031mg, 33%) as a pale yellow oil.

¹H NMR (200 MHz, CDCl₃) δ (ppm) 7.72 (d, J=2.2 Hz, 1H), 7.45 (dd, J=8.6,2.2 Hz, 1H), 7.08 (d, J=8.6 Hz, 1H), 5.78 (br s, 1H).

¹³C NMR (75 MHz, CDCl₃) δ (ppm) 158.4, 138.3, 134.4, 119.1, 115.3,112.9, 112.6.

MS m/z 229 (M−1).

(ii) Acetic acid 4-acetylsulfanyl-2-bromo-phenyl ester

A mixture of 1 (615 mg, 2.67 mmol) and Na₂S-9H₂O (706 mg, 2.94 mmol) inMeCN (25 mL) was heated at 80° C. for 1 h. After cooling to 23° C.acetic anhydride (1.3 mL, 13.35 mmol) was added and the reaction stirredat 23° C. for 1 h. The solution was diluted with brine and extractedwith CH₂Cl₂, dried (Na₂SO₄) and evaporated. Purification by silica gelflash chromatography afforded 2 (acetic acid4-acetylsulfanyl-2-bromo-phenyl ester) (630 mg, 82%) as a yellow oil.

¹H NMR (200 MHz, CDCl₃) δ (ppm) 7.67 (d, J=2.0 Hz, 1H), 7.37 (dd, J=8.4,2.0 Hz, 1H), 7.18 (d, J=8.4 Hz, 1H), 2.42 (s, 3H), 2.38 (s, 3H).

¹³C NMR (75 MHz, CDCl₃) δ (ppm) 193.3, 168.6, 149.6, 139.1, 134.9,127.4, 124.7, 117.1.

MS m/z 290 (M+1).

(iii) Acetic acid 4-thio-2-bromo-phenyl ester

To a solution of 2 (630 mg, 2.18 mmol) in MeOH (20 mL) sodiumthiomethoxide (153 mg, 1M in MeOH, 2.18 mmol) was added at 23° C. Afterstirring for 1 h the reaction was poured over an aqueous solution of HCl5% and extracted with CH₂Cl₂, dried (Na_(S)SO₄) and evaporated to yield3. The crude 3 (530 mg) was used in the next reaction.

¹H NMR (200 MHz, CDCl₃) δ (ppm) 7.53 (d, J=2.2 Hz, 1H), 7.22 (dd, J=8.4,2.2 Hz, 1H), 6.99 (d, J=8.4 Hz, 1H), 2.34 (s, 3H).

MS m/z 246 (M−1).

(iv)2-Bromo-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-(exo)-ylsulfanyl)-phenol

A mixture of crude 3 (530 mg, 2.14 mmol), methanesulfonic acid8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl ester (470 mg, 2.14 mmol) andK₂CO₃ (593 mg, 4.36 mmol) in acetone (50 mL) was heated at 65° C. for 20h the mixture was diluted with brine and extracted with CH₂Cl₂, dried(Na₂SO₄) and evaporated. The crude was purified first by C18 silica gelcartridges (H₂O→H₂O—MeOH→MeOH) and finally by reverse phase HPLC toyield 2-bromo-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-phenol(174 mg, 22%) as a white solid.

¹H NMR (200 MHz, CDCl₃) δ (ppm) 7.62 (d, J=2.2 Hz, 1H), 7.31 (dd, J=8.4,2.2 Hz, 1H), 6.89 (d, J=8.4 Hz, 1H), 3.87-3.84 (m, 2H), 3.31 (sp, J=5.1Hz, 1H), 2.70 (s, 3H), 2.31-2.24 (m, 2H), 2.12-1.85(m, 7H).

¹³C NMR (75 MHz, CDCl₃) δ (ppm) 157.0, 141.2, 137.4, 123.9, 118.2,111.5, 65.9, 39.7, 38.6, 37.7, 25.3.

MS m/z 329 (M+1).

EXAMPLE 193-Methyl-4-(8-methyl-8-aza-bicyclo[3,2,1]oct-3-(exo)-ylsulfanyl)-phenol,trifluoroacetate salt

(i) 3-methyl-4-thiocyanato-phenol

To an ice-cooled suspension of Pb(SCN)₂ (4.48 g, 13.9 mmol) in drymethylene chloride (100 mL), PhICl₂ (3.04 g, 11.1 mmol), preparedaccording to D. Koyuncu et al., J. Chem. Res. (S) 1990, 21, was addedand the resulting mixture was stirred for 40 min at 0° C. undernitrogen. M-cresol (1 g, 1 mL, 9.2 mmol) was added. The mixture wasstirred at room temperature for 2 h, and filtered through a celite padwashing extensively with methylene chloride. After addition of silicagelto the filtrate and evaporation of solvents, the mixture was purified byflash chromatography (10% ethyl acetate/hexane) to afford 1.48 g (97%)of the title compound.

Ion Electrospray Mass Spectrum M−1: 164.

¹H NMR (200 MHz, CDCl₃) δ (ppm): 7.50 (d, J=5.8 Hz, 1H), 6.81 (d, J=1.8Hz, 1H), 6.72 (dd, J=5.8 Hz, 1.8 Hz, 1H), 5.18 (br s, OH), 2.50 (s, 3H);

¹³C NMR (50 MHz, CDCl₃) δ (ppm): 157.3, 142.3, 135.0, 117.6, 113.9,111.8, 110.8.

(ii) 4-Mercapto-3-methyl-phenol

To a hot (85° C.) solution of the intermediate from step (i) (1.48 g,8.97 mmol) in absolute ethanol (60 mL) under nitrogen, sodium sulfidenonahydrate (2.60 g, 10.76 mmol) was added. The resulting mixture wasstirred at 85° C. for 2 h. The mixture was cooled down, made acidic withan aqueous solution of HCl (10%) and extracted with methylene chloride.The organic layer was washed once with water and brine, dried on MgSO₄anhydrous and concentrated in vacuo to give the title compoundimpurified with its disulfide (1.23 g). The mixture was quicklysubmitted to the next reaction without further treatment.

Ion Electrospray Mass Spectrum M−1: 139.

(iii)3-Methyl-4-(8-methyl-8-aza-bicyclo[3,2,1]oct-3-(exo)-ylsulfanyl)-phenol

To a solution of intermediate from step (ii) (1.23 g, 8.80 mmol) andmethanesulfonic acid 8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl ester (1.73g, 7.92 mmol) in dry dimethylformamide (30 mL) under nitrogen, potassiumcarbonate anhydrous (6.10 g, 44.0 mmol) was added. The resulting mixturewas vigorously stirred at room temperature for 18 h under nitrogen. Themixture was filtered and the solvent was removed in vacuo. The residuewas purified by reverse phase HPLC to obtain the title compound (10.2mg, 0.5%).

Ion Electrospray Mass Spectrum M+1: 264.

IR (cm⁻¹): 3200-3000, 1674, 1593, 1237, 799.

¹H NMR (200 MHz, CD₃OD) δ (ppm): 7.32 (d, J=8.2 Hz, 1H), 6.72 (d, J=2.8Hz, 1H), 6.60 (dd, J=8.2 Hz, 2.8 Hz, 1H), 3.82 (br m, 2H), 3.20 (m, 1H),2.71 (s, 3H), 2.41 (s, 3H), 2.26 (m, 2H), 2.10-1.85 (m, 6H)

¹³C NMR (75 MHz, CD₃OD) δ (ppm): 160.5, 145.9, 139.9, 122.2, 119.3,115.7, 66.4, 40.1, 39.3, 37.9, 25.7, 22.4

EXAMPLE 204-(9-Methyl-9-aza-bicyclo[3,3,1]non-3(exo)-ylsulfanyl)-phenol,trifluoroacetate salt

(i) 9-Methyl-9-aza-bicyclo[3,3,1]nonan-3-(endo)-ol

To a −78° C. cooled solution of pseudopelletierine (771 mg, 5.04 mmol),obtained from its chloro hydrate (pseudopelletierine chloride,commercially available) by treatment with saturated aqueous solution ofNaHCO₃, extracted with methylene chloride, and dried; in THF anhydrous(20 mL), a solution 1.0 M of DIBAL-H in hexane or toluene (10.8 mL, 10.8mmol) was added dropwise under N₂. The mixture was stirred and allowedto reach rt. for 3 h. The reaction was quenched with water (2 mL) andpoured into diethyl ether (60 mL). NaHCO₃ anhydrous (20 g) and Na₂SO₄anhydrous (20 g) were added. The mixture was stirred for 2 h at rt., andthen, it was filtered and the filtrate was evaporated. The residue wasthe title compound pure, 684 mg, 88%.

Ion Electrospray Mass Spectrum M+1: 156.

¹H NMR (200 MHz, CDCl₃) δ (ppm): 4.16 (m, 1H), 2.95 (br m, 2H),2.40-2.20 (m, 2H), 2.00-1.80 (m, 3H), 1.40-1.25 (m, 3H), 1.20-1.05 (m,2H)

¹³C NMR (50 MHz, CDCl₃) δ (ppm): 62.9, 51.6, 40.4, 34.8, 24.9, 14.4

(ii) 3-(endo)-Hydroxy-9-aza-bicyclo[3,3,1]nonane-9-carboxylic acidmethyl ester

To a solution of the intermediate from step (i) (615 mg, 3.97 mmol) indry chloroform (115 mL), methyl chloroformate (1.8 mL, 23.8 mmol)followed by potassium carbonate (457 mg, 4.56 mmol) were added. Themixture was heated at 80° C. and stirred under N₂ overnight. Thereaction was cooled down, quenched with water (10 mL) and extracted withchloroform. The organic layer was dried on MgSO₄ anhydrous, and thesolvent was removed in vacuo. The residue (800 mg) was purified by flashchromatography (30% ethyl acetate/hexane) to give the title compound,200 mg, 25%.

Ion Electrospray Mass Spectrum M+1: 200.

¹H NMR (300 MHz, CDCl₃) δ (ppm): 4.34 (br d, 2H), 3.56 (s, 3H), 3.53 (m,1H), 2.21 (m, 2 H), 2.17 (m, 1H), 1.50-1.30 (m, 7H).

¹³C NMR (75 MHz, CDCl₃) δ (ppm): 62.9, 51.6, 40.4, 34.8, 24.9, 14.4

(iii)3-(endo)-Methanesulfonyloxy-9-aza-bicyclo[3,3,1]nonane-9-carboxylic acidmethyl ester

To an ice-cooled solution of the intermediate from step (ii) (200 mg,1.0 mmol) in methylene chloride anhydrous, pyridine anhydrous (0.073 mL,0.9 mmol) followed by methanesulfonate chloride (0.085 mL, 1.1 mmol)were added under N₂. The mixture was stirred overnight and allowed toreach rt. The reaction was quenched with an aqueous solution of NH₄OH(15%), and extracted with methylene chloride. The organic layer waswashed with brine and dried. The solvent was removed in vacuo to givethe title compound, 210 mg, 76%.

Ion Electrospray Mass Spectrum M+1: 278.

¹H NMR (200 MHz, CDCl₃) δ (ppm): 4.63 (m, 1H), 4.50 (br m, 2H), 3.64 (s,3H), 2.99 (s, 3H), 2.42 (m, 2H), 1.80-1.60 (m, 8H).

¹³C NMR (50 MHz, CDCl₃) δ (ppm): 156.0, 74.5, 52.5, 45.0, 38.5, 32.4,29.6, 14.0

(iv)3-(exo)-(4-Hydroxy-phenylsulfanyl)-9-aza-bicyclo[3,3,1]nonane-9-carboxylicacid methyl ester

To a solution of the intermediate from step (iii) (107.1 mg, 0.39 mmol)and 4-mercaptophenol (98.3 mg, 0.78 mmol) in dry DMF (25 mL), ceasiumfluoride (118.5 mg, 0.78 mmol) was added. The mixture was heated at 60°C. and stirred overnight under N₂. The reaction was quenched with water,and extracted with ethyl acetate. The organic layer was washed withwater and dried. The solvent was removed in vacuo to give the titlecompound, which was submitted to the next reaction without furthertreatment.

Ion Electrospray Mass Spectrum M+1: 308, M−1: 306.

(v) 4-(9-Methyl-9-aza-bicyclo[3,3,1]non-3-(exo)-ylsulfanyl)-phenol,trifluoroacetate salt

To an ice-cooled solution of the intermediate from step (iv) (119.7 mg,0.39 mmol) in ethyl ether anhydrous (THF anhydrous can be used too) (2mL), lithium aluminium hydride (LAH) (74 mg, 1.95 mmol) was added. Themixture was stirred overnight under N₂ and allowed to reach rt. Thereaction was quenched with water and methanol at 0° C. (violentreaction), and filtered. The filtrate was evaporated and the residue wassubmitted to SCX collecting the desired product slightly impurified,which was purified by reverse phase HPLC to obtain the title compound,30 mg, 21%.

The structural analysis was done with the ammonium salt and the freeamine.

Ion Electrospray Mass Spectrum M+1: 264, M−1: 262

¹H NMR (500 MHz, CD₃OD) δ (ppm) for the free amine: 7.38 (d, J=8.6 Hz,2H), 6.75 (d, J=8.6 Hz, 2H), 3.68 (m, 1H), 3.50 (br s, 2H), 2.82 (s,3H), 2.25-2.15 (m, 6H), 2.03-1.85 (m, 3H), 1.60 (m, 1H).

¹³C NMR (150 MHz, CD₃OD) δ (ppm) for the ammonium salt. Two N-methylinvertomers were detected depending on the N-methyl position. Both aredescribed:

A: 158.6, 137.2, 120.6, 115.9, 56.2, 38.8, 37.9, 36.9, 20.9, 17.8.

B: 158.5, 136.9, 120.3, 115.9, 55.7, 38.5, 36.9, 29.2, 28.8, 17.5.

EXAMPLE 215-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]-2-pyridinylamine

(i) 8-methyl-3-[(6-nitro-3-pyridinyl)thio]-8-azabicyclo[3.2.1]octane.

A mixture of (8-methyl-8-azabicylo[3.2.1]oct-3-yl)ethanethioate (1.24 g)and 2-nitro-5-bromopyridine (790 mg) in ethanol (15 ml) and aqueoussodium hydroxide (2M, 2 ml) was stirred at room temperature overnight.The mixture was applied directly to an SCX cartridge and elutedsequentially with methanol then 2M ammonia in methanol to yield thecrude product (500 mg). This was purified by preparative LC-MS to yield8-methyl-3-[(6-nitro-3-pyridinyl)thio]-8-azabicyclo[3.2.1]octane (50mg).

(ii) 5-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]-2-pyridinylamine.

A mixture of8-methyl-3-[(6-nitro-3-pyridinyl)thio]-8-azabicyclo[3.2.1]octane (50 mg)and tin (II) chloride dihydrate (202 mg) in ethyl acetate was heatedunder reflux for 4 days and the worked up by quenching with aqueoussodium hydrogen carbonate solution. The product was extracted into ethylacetate and the organic layer dried, filtered and concentrated to yieldthe crude aminopyridine (30 mg). The material was cleaned up on an SCXcartridge as above to yield5-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]-2-pyridinylamine (25 mg).

EXAMPLE 22 Intermediate Preparation3-chloro-4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenyltrifluoromethanesulfonate

3-Chloro-4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenol (Example72, 274 mg) was dissolved in anhydrous THF (10 ml) under nitrogen andcooled to 0° C. To this was added in one portion sodium tert-butoxide(97 mg) and the solution stirred for 10 minutes. The flask was removedfrom the ice-bath and N-phenyltrifluoromethanesulfonimide (750 mg)added. The solution was stirred at room temperature overnight. Water wasadded and the layers separated. The aqueous phase was extracted withethyl acetate and the combined organics washed with saturated sodiumhydrogen carbonate solution, dried (MgSO₄), filtered and evaporated todryness. The material was purified on an SCX cartridge elutingsequentially with methanol then 2M ammonia in methanol to provide3-chloro-4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenyltrifluoromethanesulfonate (192 mg).

EXAMPLE 23 a)3-{[2-chloro-4-(3-pyridinyl)phenyl]thio}-8-methyl-8-azabicylo[3.2.1]octane

A mixture of3-chloro-4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenyltrifluoromethanesulfonate (215 mg), lithium chloride (70 mg),triphenylarsine 32 mg) and tris(dibenzylideneacetone)-dipalladium (0)(20 mg) was stirred in N-methylpyrrolidinone (10 ml) under nitrogen for5 minutes. To this was added 3-tributylstannylpyridine (200 mg) and thesolution heated to 100° C. for 2 hours. The solution was cooled to roomtemperature and aqueous sodium hydroxide (10%) added to quench thereaction. The mixture was extracted three times with dichloromethane,the combined organics dried (MgSO₄), filtered and evaporated to dryness.The material was purified on an SCX cartridge eluting sequentially withmethanol and 2M ammonia in methanol, followed by preparative LC-MSyielding3-{[2-chloro-4-(3-pyridinyl)phenyl]thio}-8-methyl-8-azabicylo[3.2.1]octane(54 mg)

b) 8-methyl-3-{[4-(3-pyridinyl)phenyl]thio}-8-azabicyclo[3.2.1]octane

Also prepared by this procedure was8-methyl-3-{[4-(3-pyridinyl)phenyl]thio}-8-azabicyclo[3.2.1]octane (from4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenyltrifluoromethanesulfonate and 3-tributylstannylpyridine).

EXAMPLE 248-methyl-3-{[4-(5-pyrimidinyl)phenyl]thio}-8-azabicyclo[3.2.1]octane

To a mixture of 4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenyltrifluoromethanesulfonate (450 mg), 5-bromopyrimidine (187 mg), lithiumchloride (150 mg) and tetrakis(triphenylphosphine) palladium (0) (68 mg)under nitrogen were added hexamethylditin (386 mg) and dioxane (15 ml).The mixture was heated under reflux overnight and then poured into amixture of aqueous potassium fluoride (1.9 g in 13 ml water) and ethylacetate (13 ml). This mixture was stirred vigorously for 2 hours, passedthrough a sintered funnel and the layers separated. The organic phasewas washed with brine, dried (MgSO₄), filtered and evaporated. The crudematerial was purified on an Isco CombiFlash device, followed byUV-guided LC to yield8-methyl-3-{[4-(5-pyrimidinyl)phenyl]thio}-8-azabicyclo[3.2.1]octane (45mg)

EXAMPLE 25 a) [1,1′-biphenyl]-4-yl 8-methyl-8-azabicyclo[3.2.1]oct-3-ylsulfide

To a mixture of 4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenyltrifluoromethanesulfonate (0.4 g) and phenylboronic acid (0.25 g) in DMF(5 ml) were added triethylamine (0.58 ml) followed bydichlorobis(triphenylphosphine) palladium (II) (0.04 g). The solutionwas heated at 90° C. for 4 hours, cooled to room temperature and dilutedwith ethyl acetate. This was washed with saturated aqueous sodiumhydrogen carbonate solution, then brine, dried (MgSO₄), filtered andevaporated. Partial clean up was achieved using preparative LC-MS. Themixture was stirred with aqueous sodium hydroxide solution (0.5M) tohydrolyse residual triflate to the phenol. The product was extractedinto ethyl acetate, still however contaminated with some of the phenol.The material was loaded onto a PE-AX column and eluted with methanolwith the final clean up by preparative LC-MS to yield[1,1′-biphenyl]-4-yl 8-methyl-8-azabicyclo[3.2.1]oct-3-yl sulfide.

Also prepared by this procedure from4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenyltrifluoromethanesulfonate and the appropriate arylboronic acid were:

-   b)    N-{4′-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio][1,1′-biphenyl]-3-yl}acetamide-   c)    8-methyl-3-{[4-(3-pyridinyl)phenyl]thio}-8-azabicyclo[3.2.1]octane-   d)    3-{[2′,4′-dichloro(1,1′-biphenyl]-4-yl]thio}-8-methyl-8-azabicylo[3.2.1]octane-   e)    3-{[4-(1-benzofuran-2-yl)phenyl]thio}-8-methyl-8-azabicylo[3.2.1]octane-   f)    3-{[4-(5-carboxamido-3-pyridinyl)phenyl]thio}-8-methyl-8-azabicyclo[3.2.1]octane-   g)    3-{[4-(3-carboxamido-phenyl)phenyl]thio}-8-methyl-8-azabicyclo[3.2.1]octane-   h)    3-{[4-(3,4,5,6-dehydro-2-oxo-piperidin-5-yl)phenyl]thio}-8-methyl-8-azabicyclo[3.2.1]octane

EXAMPLE 26 a)3-chloro-4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenylformamide

A mixture of acetic acid (0.96 g) and formic acid (0.53 g) was heatedunder reflux for 2 hours. To this was added3-chloro-4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenylamine (265mg) and heating continued for 1.5 hours. The crude mixture was placed onan SCX cartridge and eluted with methanol followed by 2M ammonia inmethanol. The impure product was then subjected to flash chromatographyon silica gel (gradient elution with increasing percentage of methanolin chloroform) to yield material of 93% purity. Final clean up bypreparative LC-MS gave3-chloro-4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenylformamide(40 mg)

b) 4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenylformamide

Prepared in an analogous manner was4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenylformamide.

EXAMPLE 27 a)N-{4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenyl]-4-thiazolecarboxamide

A mixture of 4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenylamine(50 mg), 4-carboxythiazole (52 mg), 1-hydroxybenzotriazole (61 mg) andcarbodiimide resin (1.7 mmol/g, 470 mg) in DMF (7 ml) was stirred atroom temperature for 3 days. The mixture was filtered then passedthrough an SCX cartridge, eluting with methanol followed by 2M ammoniain methanol, providingN-{4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenyl]-4-thiazolecarboxamideas a white solid (55 mg)

Prepared in a similar fashion were:

-   b)    N-{4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenyl]-1,2,3-thiadiazole-4-carboxamide-   c)    N-{4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenyl]-3-thiophenecarboxamide-   d)    N-{3-Chloro-4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenyl]-3-thiophenecarboxamide

EXAMPLE 28

Stock solutions of4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenylamine (“thesubstrate”, 0.05M), 1-hydroxybenzotriazole (“the reagent”, 0.1M) and aset of 24 carboxylic acids (“the monomers”, 0.1M) were all prepared inDMF. Each well of a 24-well RPS plate was loaded with carbodiimide resin(loading 1.7 mmol/g, 59 mg) and then each treated with 0.5 ml of thesubstrate solution, the reagent solution and a monomer solution. Thesewere stirred at room temperature for 72 hours, filtered from the resin,passed through SCX cartridges eluting with methanol then 2M ammonia inmethanol and concentrated. The materials were then further purified bypreparative LC-MS to provide the carboxamides in an average yield of 67%

By this method were prepared:

-   a) N-{4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenyl]benzamide-   b)    N-{4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenyl]-4-nitrobenzamide-   c)    4-Methoxy-N-{4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenyl]benzamide-   d)    4-Isopropyl-N-{4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenyl]benzamide-   e)    4-Chloro-N-{4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenyl]benzamide-   f)    4-Methyl-N-{4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenyl]benzamide-   g)    N-{4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenyl]-2-phenylacetamide-   h)    N-{4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenyl]-2-(4-methylphenyl)acetamide-   i)    N-{4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenyl]-2-(4-methoxyphenyl)acetamide-   j)    N-{4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenyl]-2-(4-fluorophenyl)acetamide-   k)    N-{4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenyl]-3-phenylpropanamide-   l)    N-{4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenyl]-4-phenylbutanamide-   m)    N-{4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenyl]propanamide-   n)    2-Methyl-N-{4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenyl]propanamide-   o)    2,2-Dimethyl-N-{4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenyl]propanamide-   p) N-{4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenyl]butanamide-   q)    3,3-Dimethyl-N-{4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenyl]butanamide-   r)    N-{4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenyl]-3-butenamide-   s)    N-{4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenyl]cycohexanecarboxamide-   t)    N-{4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenyl]cyclopentanecarboxamide-   u)    N-{4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenyl]-2-pyridinecarboxamide-   v)    N-{4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenyl]-3-pyridinecarboxamide-   x)    N-{4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenyl]-3-thiophenecarboxamide-   y)    N-{4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenyl]-3-indolecarboxamide

EXAMPLE 29 a)N-{4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)sulfonyl]phenyl}-3-thiophenecarboxamide

To a solution ofN-{4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenyl]-3-thiophenecarboxamide(130 mg) in methanol (5 ml) was added a solution of Oxone (446 mg) inwater. The mixture was stirred at room temperature for 30 minutes andthen applied directly to an SCX cartridge. The impure product elutedwith methanol and was subjected to further clean up by preparative LC-MSto yieldN-{4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)sulfonyl]phenyl}-3-thiophenecarboxamide(75 mg).

b) 4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)sulfonyl]phenylformamide

Prepared in a similar manner was4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)sulfonyl]phenylformamide

EXAMPLE 303-(exo)-[2-Chloro-4-(pyridin-3-yloxy)-phenylsulfanyl]-8-methyl-8-azabicyclo[3.2.1]octane

A mixture of3-Chloro-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-phenol(Example 72, 1.0 eq), 3-fluoropyridine (1.0 eq) 18-crown-6 (1 eq) and37% w/w potassium-fluoride alumina in DMSO, was treated under microwavesconditions at 150° C. over 1 hour. Dichloromethane was added to themixture reaction and then the organic layer was washed with water.Separated and dry over Mg₂SO₄ and concentrated to give a crude productwhich was purified by chromatroton silicagel rotors.

MS (ES)[M+H]⁺: 361.1

EXAMPLE 313-(exo)-[2-Chloro-4-(pyridin-2-yloxy)-phenylsulfanyl]-8-methyl-8-aza-bicyclo[3.2.1]octane

To a suspension of NaH 60% (0.020 g, 0.51 mmol) in DMF anh. (2.5 ml),3-Chloro-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-phenol (0.050g, 0.17 mmol) was added and the mixture reaction stirred 15 min. Then2-chloropyrazine (0.019 g, 0.17 mmol) was added and the mixture reactionwas refluxed for 3 h. After cooling the mixture was treated with CH₂Cl₂and washed with water and brine. The organic phase was dry over MgSO₄and concentrated in vacuo. The crude was purified in silicagel to givethe desired product.

MS (ES)[M+H]⁺: 363

EXAMPLE 32 (a)3-(exo)[2-Chloro-4-(1H-[1,2,4]triazol-3-ylmethoxy)-phenylsulfanyl]-8-methyl-8-aza-bicyclo[3.2.1]octane,bis trifluoroacetic acid salt

(i)[3-Chloro-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-(exo)-ylsulfanyl)-phenoxy]-acetonitrile

To a solution of phenol (XX) (1 g, 3.53 mmol) in dry dimethylformamide(34 mL) at r.t. under nitrogen, cesium carbonate (2.3 g, 7.06 mmol) wasadded. The mixture was stirred for 15 min and then chloroacetonitrile(0.225 mL, 3.6 mmol) was added dropwise. The reaction mixture wasstirred at r.t. for 3 h and was diluted with methylene chloride. Theresulting mixture was washed with water and the aqueous phase extractedwith methylene chloride (×3). The combined organic phase was dried oversodium sulfate, filtered and evaporated to dryness to obtain 1.1 g (97%)of titled compound which was submitted directly to the next reaction.

EI-MS: 323 (M+1)

¹H NMR (300 MHz, CD₃OD) δ (ppm) 7.55 (d, J=8.7 Hz, 1H), 7.21 (d, J=2.8Hz, 1H), 7.00 (dd, J=8.7, 2.8 Hz, 1H), 5.01 (s, 2H), 3.42 (sept, J=8.9Hz, 1H), 3.20 (br s, 2H), 2.26 (s, 3H), 2.08 (m, 2H), 1.79 (d, J=2.8 Hz,2H), 1.7 (d, J=2.0 Hz, 2H), 1.64 (d, J=8.5 Hz, 2H).

¹³C NMR (300 MHz, CD₃OD) δ (ppm) 158.3, 139.6, 127.6, 117.8, 116.6,115.2, 115.4, 62.8, 54.6, 39.8, 38.9, 38.6, 26.6.

(ii)3-(exo)[2-Chloro-4-(1H-[1,2,4]triazol-3-ylmethoxy)-phenylsulfanyl]-8-methyl-8-aza-bicyclo[3.2.1]octane,bis trifluoroacetic acid salt

To a solution of[3-Chloro-4-(exo)(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-phenoxy]-acetonitrile(0.4 g, 1.24 mmol) in methanol (0.5 mL) at 0° C. under nitrogen sodiummethoxide (34 mg, 0.63 mmol) was added, the resulting mixture wasstirred for 30 min at that temperature and acetic acid (0.035 mL, 0.63mmol) and formylhydrazide (75 mg, 1.24 mmol) were successively added.The resulting mixture was stirred at r.t. for 15 min, evaporated,dissolved in dry dimethylformamide (2 mL) and heated at 115° C. for 90min. The mixture was cooled down, diluted with methylene chloride. Theresulting mixture was washed with water and the organic phase was driedover sodium sulfate, filtered and evaporated to dryness. The residue waspurified by SPE to obtain 0.327 g (44%, 3 steps) of titled compound.

EI-MS: 365 (M+1)

¹H NMR (200 MHz, CD₃OD) δ (ppm) 8.42 (s, 1H), 7.55 (d, J=8.7 Hz, 1H),7.24 (d, J=2.6 Hz, 1H), 7.00 (dd, J=8.7, 2.8 Hz, 1H), 5.21 (s, 2H), 3.88(br s, 2H), 3.50 (sept, J=5.8 Hz, 1H), 2.72 (s, 3H), 2.32-1.95 (m, 8H).

¹³C NMR (300 MHz, CD₃OD) δ (ppm) 160.7, 158.4, 147.0, 140.5, 138.6,124.1, 117.9, 115.4, 65.0, 64.0, 38.9, 37.8, 36.9, 25.1.

(b)3-(exo)[2-chloro-4-(1H-[1,3,4]oxadiazol-2-ylmethoxy)-phenylsulfanyl]-8-methyl-8-aza-bicyclo[3.2.1]octanetrifluoroacetic acid salt

By proceeding in a similar manner to Example 32(a) but using ethylbromoacetate in step (i), there was prepared3-(exo)[2-chloro-4-(1H-[1,3,4]oxadiazol-2-ylmethoxy)-phenylsulfanyl]-8-methyl-8-aza-bicyclo[3.2.1]octanetrifluoroacetic acid salt.

EXAMPLE 33[3-Chloro-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-(exo)-ylsulfanyl)-phenoxy]-difluoro-aceticacid

(i)[3-Chloro-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-(exo)-ylsulfanyl)-phenoxy]-difluoro-aceticacid

To a solution of phenol (XX) (1 g, 3.53 mmol) in dry dioxane (12 mL) at0° C. under nitrogen sodium hydride (2.1 g, 88.25 mmol) andchlorodifluoroacetic acid (3 mL, 35.27 mmol) were successively added.The resulting mixture was heated at reflux for two days and cooled downto 0° C. To the cold mixture ice-water was added carefully, and theresulting mixture was evaporated in vacuo. diluted with a solution ofhydrochloric acid (10%) and extracted with methylene chloride (×2). Theorganic phase was dried over sodium sulfate, filtered and evaporated todryness. The residue was purified by SCX to obtain 0.433 g (32%) oftitled compound.

EI-MS: 378 (M+1)

¹H NMR (200 MHz, CD₃OD) δ (ppm) 7.58 (d, J=8.6 Hz, 1H), 7.37 (d, J=2.4Hz, 1H), 7.19 (dd, J=8.6, 2.6 Hz, 1H), 3.88 (br s, 2H), 3.60 (sept,J=6.0 Hz, 1H), 2.74 (s, 3H), 2.32-1.91 (m, 8H).

¹³C NMR (300 MHz, CD₃OD) δ (ppm) 164.2 (d, J=34.2 Hz), 151.8, 137.9,135.7, 128.2, 122.6, 120.2, 116.7 (t, J=450 Hz), 64.4, 38.2, 36.9, 35.2,23.9.

EXAMPLE 342-[3-Chloro-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-(exo)-ylsulfanyl)-phenoxy]-N-ethyl-acetamide,formic salt

(i) 2-bromo-N-ethyl-acetamide

To a solution of ethylamide (0.056 mL, 1 mmol) plus triethylamine (0.4mL, 2.9 mmol) in dry DCM (5 mL), bromoacetyl-bromide (0.2 mL, 2.3 mmol)was added at −78° C. under N₂ atmosphere (exotermic reaction). Themixture was stirred and allowed to reach room temperature until thestarting material had disappeared by TLC (eluent:DCM/MeOH/NH₄OH drops,UV as developer, dark brown colour). The reaction was quenched with anaqueous solution of NaHCO₃ (5%). Both phases were stirred vigorously,and then they were separated with a column (empty cartridge) withhydrophobic resin 5 micros called FPTE (12 mL capacity). The organiclayer was collected in a 13/100 tube and the solvent was evaporated inthe N₂ stream. The residue was dissolved in dry DMF (2 mL) to have asolution of 2-bromo-N-ethyl-acetamide 0.5N to use in next step.

ii)2-[3-Chloro-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-(exo)-ylsulfanyl)-phenoxy]-N-ethyl-acetamide,formic salt

To a suspension of3-Chloro-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-phenol (50mg, 0.18 mmol) plus2-tert-butylimino-2-diethylamino-1,3-dimethylperhydro-1,3,2-diaza-phosphorine(BEMP) on polystyrene (2.2 mmol base/g) (509 mg, 1.08 mmol) in dry DMF(1 mL) in a glass vial charged with two caps and with a polystyrenefrit., a solution of 2-bromo-N-ethyl-acetamide (0.5N in DMF) (0.36 mL,0.18 mmol) made in the step i, was added at room temperature. Themixture was stirred for 16 h and checked by MS. The reaction solutionwas filtered and the resin was washed with MeOH several times. Thecombined organic fractions (DMF plus MeOH) were evaporated and theresidue (45 mg) was submitted to HPLC purification (preparative LC-MS)collecting the title compound (10 mg)

MS (ES) [M+1]: 368

¹H NMR δ (ppm) (200 MHz, MeOD): 8.48 (br s, H—COOH, 1H), 7.55 (d, J=8.6Hz, 1H), 7.17 (d, J=2.7 Hz, 1H), 6.93 (dd, J=2.9, 8.9 Hz, 1H), 4.49 (s,2H), 3.82 (m, 2H), 3.49 (m, 1H), 3.28 (m, 2H), 2.69 (s, 3H), 2.30-1.90(m, 8H), 1.12 (t, J=7.3 Hz, 3H)

Prepared in a similar fashion were prepared the formic salts of:

-   2-[3-Chloro-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-(exo)-ylsulfanyl)-phenoxy]-N,N-diethyl-acetamide,-   2-[3-Chloro-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-(exo)-ylsulfanyl)-phenoxy]-N-isopropyl-acetamide,-   2-[3-Chloro-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-(exo)-ylsulfanyl)-phenoxy]-N-cyclohexyl-acetamide,-   N-Benzyl-2-[3-chloro-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-(exo)-ylsulfanyl)-phenoxy]-acetamide,-   2-[3-Chloro-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-(exo)-ylsulfanyl)-phenoxy]-N-(4-fluoro-benzyl)-acetamide,-   2-[3-Chloro-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-(exo)-ylsulfanyl)-phenoxy]-N-(2,4-difluoro-benzyl)-acetamide,

EXAMPLE 353-(exo)-(4-Benzyloxy-2-chloro-phenylsulfanyl)-8-methyl-8-aza-bicyclo[3.2.1]octane

3-Chloro-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-phenol (0.050g, 0.17 mmol), PPh₃P (0.129 g, 0.49 mmol), and benzylic alcohol (0.026ml, 025.mmol) were dissolved in DMF and to this solution DIAD was added(0.088 g, 0.44 mmol). The mixture reaction was treated at 150° C. undermicrowaves conditions over 3 hours. The mixture reaction dissolved inmethanol was passed through a SCX cartridge then eluting 2M ammonia inmethanol and concentrated. The material was then further purified bypreparative LC-MS to provide the desired product.

MS (ES) [M+H]⁺: 374

By this method were prepared:

-   3-(exo)-[2-Chloro-4-(2-trifluoromethyl-benzyloxy)-phenylsulfanyl]-8-methyl-8-aza-bicyclo[3.2.1]octane-   3-(exo)-[2-Chloro-4-(3-trifluoromethyl-benzyloxy)-phenylsulfanyl]-8-methyl-8-aza-bicyclo[3.2.1]octane-   3-(exo)-[2-Chloro-4-(2-methoxy-benzyloxy)-phenylsulfanyl]-8-methyl-8-aza-bicyclo[3.2.1]octane-   3-(exo)-[2-Chloro-4-(3-methoxy-benzyloxy)-phenylsulfanyl]-8-methyl-8-aza-bicyclo[3.2.1]octane-   3-(exo)-[2-Chloro-4-(3-fluoro-benzyloxy)-phenylsulfanyl]-8-methyl-8-aza-bicyclo[3.2.1]octane-   3-(exo)-[2-Chloro-4-(3,5-difluoro-benzyloxy)-phenylsulfanyl]-8-methyl-8-aza-bicyclo[3.2.1]octane-   3-(exo)-[4-(Benzo[1,3]dioxol-5-ylmethoxy)-2-chloro-phenylsulfanyl]-8-methyl-8-aza-bicyclo[3.2.1]octane-   3-(exo)-[2-Chloro-4-(2,6-difluoro-benzyloxy)-phenylsulfanyl]-8-methyl-8-aza-bicyclo[3.2.1]octane-   3-(exo)-[2-Chloro-4-(thiophen-2-ylmethoxy)-phenylsulfanyl]-8-methyl-8-aza-bicyclo[3.2.1]octane-   3-(exo)-[2-Chloro-4-(imidazol-2-ylmethoxy)-phenylsulfanyl]-8-methyl-8-aza-bicyclo[3.2.1]octane

EXAMPLE 363-[3-Chloro-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-(exo)-ylsulfanyl)-phenyl]-propionicacid, N-trifluoroacetic salt

(i)3-[3-Chloro-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-(exo)-ylsulfanyl)-phenyl]-acrylicacid ethyl ester

To a stirred solution of trifluoro-methanesulfonic acid3-chloro-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-phenyl ester(306 mg, 0.74 mmol) in dry DMF (2 mL) under N₂ atmosphere at roomtemperature, were sequentially added triethylamine (0.11 mL, 0.81 mmol),ethyl acrylate (0.16 mL, 1.48 mmol), triphenylphosphine (7.87 mg, 0.03mmol) and palladium acetate (2.24 mg, 0.01 mmol). The mixture wasdegassed and stirred for 2 h at 100° C.

As the reaction hadn't been done by MS (ES), the duplicated quantitiesof the reactants were added to the reaction, degassed again, and stirredat 100° C. for 48 h. The reaction was quenched with water, and thesolvent was removed in vacuo. The residue was dissolved in methanol andsubmitted to SCX cartridge. The ammonia fraction was submitted to aflash column chromatography on silica gel (using DCM/solution 2M NH₃ inMeOH) collecting the title compound mixed with starting material (150mg) and3-chloro-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-phenol,product of the hydrolysis of the starting material. The mixture ofstarting material and the title compound was submitted to next reactionwithout further purification.

MS (ES) [M+1]=366

(ii)3-[3-Chloro-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-(exo)-ylsulfanyl)-phenyl]-acrylicacid

To a solution of the intermediate from step (i) (150 mg) in ethanol (4mL), an aqueous solution of sodium hydroxide (20%) was added at roomtemperature. The reaction was stirred for 16 h. The reaction was checkedby MS (ES), and the starting material had been converted in the titlecompound. Then, the solvent was removed in vacuo, and the residue wassubmitted to SPE cartridge using 0.05% TFA in water/acetonitrile,collecting the title compound mixed with the3-chloro-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-phenol. (123mg)

MS (ES) [M+1]=338

(iii)3-[3-Chloro-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-(exo)-ylsulfanyl)-phenyl]-propionicacid. N-trifluoroacetic salt

To a solution of the intermediate from step (ii) (123 mg) in dry DMF,palladium in active carbon (10%) (820 mg) was added. The mixture wasdegassed and stirred under hydrogen atmosphere for 16 h. The solvent wasremoved in vacuo and the residue was submitted to SAX cartridge, andHPLC purification to get the title compound.

MS (ES) [M+1]: 339

EXAMPLE 37[3-Chloro-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-(exo)-ylsulfanyl)-phenyl]-pyridin-3-yl-amine

In a dry schlenk flask we charged Pd₂(dba)₃ (2.0 mmol/%), BINAP (2.0mmol/%) and CsCO₃ (0.054 g, 0.168 mmol), evacuated and filled withArgon. Then trifluoro-methanesulfonic acid3-chloro-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-phenyl ester(0.050 g, 0.12 mmol) and 3-aminopyridine (0.0135, 0.144 mmol) were addedunder Argon. Toulene was added to this mixture and the septum wasreplaced with a teflon screwcap heating the reaction at 100° C.overnight. The reaction was concentrated to dryness and purified bychromatography in SiO₂ (CH₂Cl₂/2M NH₄OH/MeOH: 9.5/0.5) to yield thedesired product.

MS (ES) [M+H]⁺: 361

EXAMPLE 38Exo-5-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-1H-indazole

(i) 1-H-Indazole-5-thiol

5-Aminoindazole (10 g, 0.075 mol) was suspended in water (150 ml) andheated to 60° C. Concentrated HCl (26 ml) was added to form the HCl saltand the mixture stirred at 60° C. for 30 minutes before cooling to −3°C. in an ice/MeOH bath. Diazotization was performed by dropwise additionof a pre-chilled (˜3° C.) solution of sodium nitrite (5.18 g, 0.075 mol)in water (75 ml), beneath the surface of the stirring solution. Thetemperature was maintained below 0° C. for 30 minutes. Meanwhile,potassium ethyl xanthate (18.03 g, 0.112 mol) was dissolved in water andheated to 70° C. The diazonium species was then added slowly to the hotsolution and stirring continued at this temperature for 2 hours. Thereaction mixture was allowed to cool then was extracted with diethylether (4×200 ml), washed with 2N NaOH (2×200 ml) then water (200 ml) andbrine (200 ml). The organic extracts were dried (MgSO₄) and concentratedin vacuo to yield the xanthate as a viscous brown oil (4.96 g, 28%). Thecrude xanthate was slowly added as a solution in THF (125 ml) viacannula to a solution of LiAlH₄ (75 ml, 1M in THF, 0.075 mol) in THF (50ml) at 0° C. Exhaust gases from this reaction were bubbled throughbleach. When addition was complete, the reaction mixture was heated toreflux for 1 hour then re-cooled to 0° C. and quenched by carefuladdition of water (86 ml). The aluminium residues were then destroyed byaddition of concentrated HCl (45 ml). The organic layer was separatedand the aqueous phase was extracted with diethyl ether (3×150 ml) thenthe combined organic phases were dried (MgSO₄) and concentrated in vacuoto furnish the impure thiol as a yellow solid (2.55 g, 23% over twosteps); this was used immediately without further purification; LCMSretention time ˜3.09 min m/z 151.1 [(M+H)⁺, 54.6%] plus a small amountof disulfide; LCMS retention time ˜4.5 min 299.0 [(M+H)⁺, 6.1%] andother impurities.

(ii) Exo-5-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-1H-indazole

1-H-Indazole-5-thiol (1.27 g, 8.47 mmol) was stirred with CsF (1.29 g,8.47 mmol) and ENDO-methanesulfonic acid8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl ester (2.04 g, 9.31 mmol) in DMF(15 ml) for 18 hours at room temperature. The mixture was then heated to60° C. for a further 24 hours. The DMF was removed by washing thereaction mixture onto an SCX-2 cartridge, washing with MeOH, theneluting the product with NH₃/MeOH (˜2M) and concentrating in vacuo. Thecrude material was purified by column chromatography (eluent; 5% MeOH inDCM) to furnish slightly impure product. This was further purified bytrituration with CHCl₃/ether, which afforded the title compound as anoff-white solid (77 mg, 3.3%);

δ_(H) (300 MHz, CDCl₃); 1.61-1.68 (2H, m), 1.78-1.84 (2H, m), 1.89-1.98(2H, m), 2.02-2.10 (2H, m), 2.24 (3H, s, NCH₃), 3.09-3.21 (1H, m, CH),3.25 (2H, br s, 2×CH), 7.20-7.23 (1H, m, Ar—H), 7.39-7.40 (1H, m, Ar—H),7.89 (1H, s, Ar—H), 7.98 (1H, s, Ar—H), 11.57 (1H, br s, NH);

LCMS retention time ˜1.73, m/z 274.1 [(M+H)⁺, 100%].

EXAMPLE 39Exo-5-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-1H-indole

By proceeding in a similar manner to Example 38 but using 5-aminoindolethere was prepared the title compound as a pale yellow solid.

δ_(H) (300 MHz, CDCl₃); 1.52-1.56 (2H, m), 1.70-1.79 (2H, m), 1.80-1.89(2H, m), 1.95-2.05 (2H, m), 2.25 (3H, s, NCH₃), 3.12-3.21 (3H, m, 3×CH),6.50 (1H, br s, Ar—H), 7.21-7.23 (1H, m, Ar—H), 7.30 (2H, s, 2×Ar—H),7.81 (1H, s, Ar—H), 8.72 (1H, br s, NH); LCMS retention time ˜2.5 min,m/z 273.1 [(M+H)⁺, 100%].

EXAMPLE 40Exo-5-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-1H-benzotriazole

By proceeding in a similar manner to Example 38 but using5-aminobenzotriazole there was prepared the title compound as a paleyellow solid.

δ_(H) (300 MHz, CDCl₃); 1.75-1.82 (2H, m), 1.89-2.00 (2H, m), 2.08-2.22(4H, m), 2.37 (3H, s, NCH₃), 3.21-3.38 (1H, m, CH), 3.45 (2H, br s,2×CH), 6.29 (br s, NH), 7.30-7.35 (1H, m, Ar—H), 7.60-7.64 (1H, m,Ar—H), 8.06 (1H, s, Ar—H); LCMS retention time 1.15, m/z 275.1 [(M+H)⁺,100%].

EXAMPLE 417-Chloro-1-methyl-exo-6-(8-methyl-8-aza-bicyclo[3.2.1]oct-6-en-3-ylsulfanyl)-1,3-dihydro-benzoimidazole-2-thione

(i) ENDO-Methanesulfonic acid 8-methyl-8-aza-bicyclo[3.2.1]oct-6-en-3-ylester

Tropenol hydrochloride (15.03 g, 0.085 mol) and triethylamine (11.9 ml,0.085 mol) in CHCl₃ (100 ml) were cooled to −10° C. then methanesulfonylchloride (6.6 ml, 0.085 mol) in CHCl₃ (50 ml) was added dropwise. Asecond equivalent of MsCl (6.6 ml, 0.085 mol) was added after 2 hoursand a third equivalent (6.6 ml, 0.085 mol) after 18 hours. The reactionmixture was stirred for 30 minutes after the last addition, thenquenched with NH₃/water (2:1, 300 ml) and stirred for another 30minutes. The solution was diluted with CHCl₃, then washed with water(150 ml) and brine (150 ml), dried (MgSO₄) and concentrated in vacuo toyield the product as a cream solid (13.48 g, 80%); δ_(H) (300 MHz,CDCl₃); 1.95-1.99 (1H, m, CH), 2.25-2.31 (δ_(H), m, NCH₃, 2×CH),2.33-2.36 (1H, m, CH), 2.94 (3H, s, SCH₃), 3.42 (2H, br s, 2×CH),4.91-4.96 (1H, m, CH), 6.06 (2H, s, 2×CH);

(ii) Exo-thioacetic acid S-(8-methyl-8-aza-bicyclo[3.2.1]oct-6-en-3-yl)ester

To a stirring solution of methanesulfonic acid8-methyl-8-aza-bicyclo[3.2.1]oct-6-en-3-yl ester (7.95 g, 0.0366 mol) inTHF/DMF (100 ml, 2% DMF in THF) was added potassium thioacetate (8.37 g,0.0733 mol) and the reaction heated to reflux under nitrogen for 24hours. Silica gel was added and the crude product was concentrated invacuo. The resultant powder was purified by column chromatography(eluent; 5-15% MeOH in DCM). The undesired endo isomer was isolated as abrown oil (1.89 g) and the desired thioacetate was obtained as a 3:1 mixof exo:endo isomers (0.670 g), which was used without furtherpurification; δ_(H) (300 MHz, CDCl₃) 1.62-1.67 (m, CH), 1.77-1.81 (4H,m), 2.24-2.28 (m, 4×CH₃), 2.47-2.57 (2H, m) 3.48 (2H, br s, 2×CH), 3.52(2H, br s, 2×CH), 3.61-3.73 (1H, m, CH), 3.99-4.03 (1H, m, CH), 5.99(2H, s, 2×CH), 6.03 (2H, s, 2×CH).

(iii)[2-Chloro-exo-3-(8-methyl-8-aza-bicyclo[3.2.1]oct-6-en-3-ylsulfanyl)-6-nitro-phenyl]-methylamine

(2,3-Dichloro-6-nitro-phenyl)-methylamine (620 mg, 2.82 mmol) andexo-thioacetic acid S-(8-methyl-8-aza-bicyclo[3.2.1]oct-6-en-3-yl) ester(670 mg, 3.38 mmol) in ethanol (20 ml) were degassed then NaOH (2.8 ml)was added. After stirring for 1 hour the reaction mixture was separatedinto two portions and crudely purified by elution through an SCX-2cartridge. The column was washed with MeOH then the product was elutedwith NH₃/MeOH (˜2M) and concentrated in vacuo. Purification of thiscrude material by column chromatography (eluent 0-10% MeOH in DCM)yielded the exo isomer as an orange oil (190 mg); δ_(H) (300 MHz,CDCl₃); 1.90-1.99 (4H, m, 2×CH₂), 2.25 (3H, s, NCH₃), 3.09-3.12 (3H, m,NHCH₃), 3.40-3.58 (3H, m, CH, 2×CH), 6.01 (2H, s, 2×CH), 6.55-6.61 (1H,m, Ar—H), 7.08 (1H, br s, NH), 7.88-7.92 (1H, m, Ar—H) and the endoisomer as an orange oil (170 mg).

(iv)3-Chloro-N²-methyl-exo-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-6-en-3-ylsulfanyl)-benzene-1,2-diamine

[2-Chloro-3-(8-methyl-8-aza-bicyclo[3.2.1]oct-6-en-3-ylsulfanyl)-6-nitro-phenyl]-methyl-amine(190 mg, 0.560 mmol) and SnCl₂.2H₂O (630 mg, 2.80 mmol) were heated tobetween 60-70° C.; the colour of the reaction changed from orange todarker orange. Stirring was continued for 2 hours then the solution wasfiltered to remove a yellow precipitate, washed with NaHCO₃ (50 ml) andextracted with ethyl acetate (3×50 ml). The organic extracts werecombined, dried (MgSO₄) and concentrated in vacuo to yield the crudediamine as an orange oil (86 mg, 50%) which was used without furtherpurification; δ_(H) (300 MHz, CDCl₃); 1.62-1.74 (4H, m, 2×CH₂), 2.15(3H, s, NCH₃), 2.61 (3H, s, NHCH₃), 2.92-3.06 (1H, m, CH), 3.38 (2H, brs, 2×CH), 5.81 (2H, s, 2×CH), 6.46-6.48 (1H, m, Ar—H), 7.00-7.05 (1H, m,Ar—H); LCMS retention time ˜1.12 min, m/z 310.1 [(M+H)⁺, 58%]

(v)7-Chloro-1-methyl-exo-6-(8-methyl-8-aza-bicyclo[3.2.1]oct-6-en-3-ylsulfanyl)-1,3-dihydro-benzoimidazole-2-thione

3-Chloro-N²-methyl-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-6-en-3-ylsulfanyl)-benzene-1,2-diamine(86 mg, 0.278 mmol) and triethylamine (0.155 ml, 1.11 mmol) in THF (3ml) were cooled to 0° C. and thiophosgene (0.023 ml, 0.306 mmol) wasadded. Stirred for 1 hour at 0° C. then the mixture was concentrated invacuo. Purification by mass-guided preparative LCMS furnished the aceticacid salt of the product in solution. This was converted to the freebase by application of this aqueous solution to an SCX-2 cartridge,washing with MeOH then elution of the product with NH₃/MeOH (˜2M). Theammoniacal solution was concentrated in vacuo to yield the titlecompound as a yellow solid (42 mg, 43%); δ_(H) (300 MHz, CDCl₃);1.91-2.00 (2H, m, 2×CH), 2.10 (3H, s, NCH₃), 2.19-2.31 (2H, m, 2×CH),3.01-3.15 (1H, m, CH), 3.80 (2H, br s, 2×CH), 6.02 (2H, s, 2×CH),6.48-6.50 (1H, m, Ar—H), 7.28-7.31 (1H, m, Ar—H); LCMS retention time˜1.78 min, m/z 352.1 [(M+H)⁺].

EXAMPLE 425-Chloro-6-[endo-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)thio]-1,4-dihydro-2H-3,1-benzoxazin-2-one

(i) Methyl-2,3-dichloro-6-nitrobenzoate

To a stirred solution of methyl-2,3-dichlorobenzoate (10 g, 48.7 mmol)in concentrated sulphuric acid (40 ml), cooled to 5° C., was addeddropwise, (at such a rate to keep the reaction temperature <25° C.),concentrated nitric acid (8.4 ml, 82.9 mmol). The mixture was thenstirred at ambient temperature for 2 h.

The mixture was poured slowly into water (200 ml) and stirred for 2 h.The suspension was filtered, the filter cake washed with more water onthe sinter, and dried in vacuo to give the crude product as a whitesolid (10.3 g). The crude product was recrystallized from hexane, thecrystallised solid (5-nitro isomer) removed by filtration, and themother liquors evaporated in vacuo. The resultant white solid wasrecrystallized from hexane and the crystallised solid collected byfiltration and dried in vacuo to give the product as a white crystallinesolid (1.3 g).

(ii)Methyl-2-chloro-3-[endo-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)thio]-6-nitrobenzoate

To a stirred solution of methyl-2,3-dichloro-6-nitrobenzoate (3.6 g,14.4 mmol) in ethanol (75 ml) was added a solution ofENDO-methanesulfonic acid 8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl ester(4.3 g, 21.6 mmol) in ethanol (75 ml) and then 2M sodium hydroxide (10.8ml, 21.6 mmol). The mixture was stirred under nitrogen at ambienttemperature for 24 h. The mixture was evaporated in vacuo to give aviscous orange oil (10.7 g). The crude product was purified by flashchromatography (SiO₂; CH₂Cl₂ 5% MeOH 0.1% NH₄OH) to give the product asa yellow solid (3.0 g).

(iii)Methyl-6-amino-2-chloro-3-[endo-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)thio]benzoate

To a stirred solution ofmethyl-2-chloro-3-[endo-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)thio]-6-nitrobenzoate(3.0 g, 8.1 mmol) in ethyl acetate (400 ml) was added tin chloridedihydrate (9.14 g, 40.5 mmol) and the mixture was heated under refluxfor 2 h.

The mixture was allowed to cool and then poured into saturated sodiumbicarbonate (400 ml). The organic phase was separated and the aqueousphase extracted 2× with ethyl acetate. The combined organic phases werewashed with (1) water and (2) saturated sodium chloride solution, dried(MgSO₄) and evaporated in vacuo to give a brown viscous oil (2.2 g). Thecrude product was purified by flash chromatography (SiO₂; CH₂Cl₂ 20%MeOH 0.1% NH₄OH) to give the product as a light-brown oil (1.76 g).

(iv){6-Amino-2-chloro-3-[endo-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)thio]phenyl}methanol

To a suspension of lithium aluminium hydride (180 mg, 4.7 mmol) in drytetrahydrofuran (5 ml) was added a solution ofmethyl-6-amino-2-chloro-3-[endo-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)thio]benzoate(800 mg, 2.35 mmol) in tetrahydrofuran (20 ml) and the mixture stirredat ambient temperature for 4 h.

The mixture was quenched with water, filtered and the filter cake washedwith ethanol. The combined filtrate and washings were evaporated invacuo to give a yellow gum (774 mg). The crude product was purified byflash chromatography (SiO₂; CH₂Cl₂ 20% MeOH 0.1% NH₄OH) to give theproduct as a light-yellow oil (408 mg).

(v)5-Chloro-6-[endo-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)thio]-1,4-dihydro-2H-3,1-benzoxazin-2-one

To a solution of{6-Amino-2-chloro-3-[endo-(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)thio]phenyl}methanol(372 mg, 1.2 mmol) and triethylamine (0.83 ml, 5.96 mmol) in chloroform(10 ml), cooled to −10° C., was added, dropwise, a 20% solution ofphosgene in toluene (0.66 ml, 1.3 mmol). The mixture was allowed to warmto ambient temperature and stirred for 2 h. The mixture was evaporatedin vacuo to give an orange solid (1.24 g). The crude product waspurified by ion-exchange chromatography (SCX 500 mg pre-washed withmethanol; washed with methanol and eluted with 2M methanolic ammonia);evaporation in vacuo gave a yellow oil (228 mg). Further purification bypreparative mass-guide LC-MS gave the acetate of the product as a yellowoil (230 mg). Final purification by ion-exchange chromatography as abovegave the free base of the title compound as a white foam (148 mg, 37%).¹H NMR (300 MHz; CD₃OD): 1.5-1.6 (2H, m, CH₂), 1.63-1.72 (4H, m, 2×CH₂),1.9-2.0 (2H, m, CH₂), 2.2 (3H, s, NCH₃), 3.2-3.35 (3H, m, 3×CH), 4.65(2H, s, O—CH₂), 6.65 (1H, d, Ar—H), 7.35 (1H, d, Ar—H). LC-MS retentiontime ˜1.4 min, m/z (FIAPOSES) 339.1 [M+H+, 100%].

EXAMPLE 43EXO-5-Chloro-6-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-1H-quinolin-2-one

(i) 6-Chloro-5-nitroquinoline

A solution of 6-chloroquinioline (5 g, 30.6 mmol) in 30 mL CH₂SO₄ wascooled to 0° C. Sodium nitrite (70 mg, 1 mmol) was added followed bycHNO₃ (2.5 mL) dropwise at a rate to keep the temperature between 0° C.and 10° C. The mixture was stirred at 0° C. for 45 mins and at roomtemperature for 1 hour. After this time, the mixture was poured into iceand c NH₃ solution added until pH=7 (with cooling). The mixture was thenfiltered and the residue dried in vacuo to give6-Chloro-5-nitroquinoline as an off-white solid (5.7 g, 89%); H (300MHz; CDCl₃) 7.85 (1H, dd), 8.05 (1H, d), 8.25 (1H, d), 8.35 (1H, d) and9.10 (1H, d).

(ii) 6-Chloro-5-nitroquinoline-N-oxide

m-Chloroperbenzoic acid (70-75% by wt, 2.7 g, 15.6 mmol) was added inportions to a stirred, ambient temperature solution of6-chloro-5-nitroquinoline (2 g, 9.6 mmol) in CHCl₃ (15 mL). The mixturewas stirred for 6 h. After this time, more CHCl₃ was added, followed by30 mL of a saturated aqueous solution of Na₂CO₃ and 1 mL 1M NaOH. Themixture was separated and the aqueous phase extracted with CHCl₃ (×2).The organic phases were combined and washed with a saturated aqueoussolution of Na₂CO₃, H₂O and brine. The organic phase was dried (MgSO₄)and the solvent removed in vacuo to give6-Chloro-5-nitroquinoline-N-oxide as a yellow solid (1.8 g, 84%); H (300MHz; CDCl₃) 7.6 (1H, m), 7.7 (1H, d), 7.95 (1H, d), 8.65 (1H, d) and8.75 (1H, d).

iii)EXO-6-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-5-nitro-quinoline-N-oxide

A mixture of 6-chloro-5-nitroquinoline-N-oxide (2.68 g, 11.7 mmol) andexo-thioacetic acid 8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl ester (3 g,15.1 mmol) in de-gassed MeOH (120 mL) was treated with 15 mL of 2M NaOHand stirred at room temperature under an atmosphere of nitrogen for 48h. The solvent was removed in vacuo and the residue purified by flashcolumn chromatography using an ISCO CombiFlash system (2×120 g column,eluent 40-50% MeOH (containing 1% NH₃) in CH₂Cl₂). The title compoundwas obtained as a yellow-brown semi-solid (90-95% pure) (2.1 g, 52%); H(300 MHz; CDCl₃) 1.9 (2H, m), 2.1 (2H, m), 2.3 (2H, m), 2.69 (2H, m),3.3 (3H, s), 3.81 (2H, m), 3.99 (1H, m), 7.70 (1H, t), 7.8 (1H, d), 8.2(1H, d), 8.7 (1H, d) and 8.8 (1H, d).

(iv)EXO-5-Amino-6-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-quinoline-N-oxide

A mixture ofEXO-6-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-5-nitro-quinoline-N-oxide(1.9 g, 5.5 mmol) and tin (II) chloride dihydrate (7 g, 27.5 mmol) inEtOAc (200 mL) was heated under reflux for 18 h. The hot solution wasfiltered and the organic phase carefully washed with 33% aq NH₃. Theresidue was washed with 33% aq NH₃ and the aqueous phase extracted withEtOAc. The organic phases were then combined, dried (MgSO₄), filteredand solvent removed in vacuo to give the title compound as a brightyellow foam (550 mg, 32%); H (300 MHz; CDCl₃) 1.49 (2H, m), 1.70 (2H,m), 1.85 (2H, m), 1.97 (2H, m), 2.24 (3H, s), 3.15 (3H, m), 5.27 (2H,bs), 7.22 (1H, t), 7.72 (2H, t), 8.04 (1H, d) and 8.48 (1H, d).

(v)EXO-5-Chloro-6-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-quinoline-N-oxide

To a stirred solution ofEXO-5-Amino-6-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-quinoline-N-oxide(500 mg, 1.6 mmol) in cHCl (4 mL) in H₂O (2 mL) cooled to −5° C. wasadded a solution of sodium nitrite (110 mg, 1.6 mmol) in H₂O (0.6 mL).After stirring at low temperature for 15 mins, the mixture was added toa stirred suspension of copper (I) chloride (630 mg, 6.3 mmol) in cHCl(1.3 mL) heated to 83-65° C. The combined mixture was stirred atelevated temperature for 5 mins. Ice was added and the mixture madealkaline with 10% NaOH, extracted with CHCl₃ (×5), washed with brine andthe organic phase dried (MgSO₄). The solvent was removed in vacuo andthe resulting residue purified by flash column chromatography using theISCO CombiFlash system (35 g column, eluent 15-30% MeOH (containing 1%NH₃) in CH₂Cl₂) to give the title compound as a colourless solid (98 mg,18%); H (300 MHz; CDCl₃) 1.65 (2H, m), 1.90 (4H, m), 2.12 (2H, m), 2.34(3H, s), 3.20 (2H, m), 3.65 (1H, m), 7.35 (1H, t), 7.65 (1H, d), 8.05(1H, d), 8.45 (1H, d) and 8.65 (1H, d).

(vi)EXO-5-Chloro-6-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-1H-quinolin-2-one

Benzoyl chloride (45 mg, 0.32 mmol) was added dropwise to a vigorouslystirred two-phase mixture ofEXO-5-Chloro-6-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-quinoline-N-oxide(90 mg, 0.27 mmol) and NaOH (25 mg, 0.62 mmol) in H₂O (0.8 mL) andCH₂Cl₂ (0.42 mL). The reaction mixture was allowed to stir at roomtemperature for 1 h and then filtered. The residue was washed withCH₂Cl₂ and H₂O and dried in vacuo. The solid was purified by LC-MS togive the acetate salt of the title compound as a colourless solid (11.3mg, 11%); H (300 MHz; CDCl₃) 2.05 (6H, m), 2.29 (2H, m), 2.65 (3H, s),3.65 (1H, m), 3.75 (2H, m), 6.75 (1H, d), 7.35 (1H, d), 7.75 (1H, d) and8.35 (1H, d).

EXAMPLE 44EXO-6-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-1H-quinolin-2-one

(i) 2-Oxo-1,2-dihydro-quinoline-6-sulfonyl chloride

To an ice bath cooled stirred slurry of 2-hydroxyquinoline (30.5 g,0.210 mol) in dichloromethane (300 cm³) was added chlorosulphonic acid(70 cm³, 1.05 mol) in 4 equal sized batches. This was left to stir atroom temperature for 2 days then slowly poured onto crushed ice. Largeamount of a white solid formed in the lower chlorinated layer. This wasfiltered off and dried in vacua to yield2-Oxo-1,2-dihydro-quinoline-6-sulfonyl chloride as a dry white solid(36.3 g); δ_(H) (300 MHz; D6 DMSO) 6.51-6.59 (1H, m, 1×Ar—H), 7.29-7.34(1H, m, Ar—H), 7.71-7.79 (1H, m, Ar—H), 7.90-7.96 (1H, m, Ar—H) and8.00-8.06 (1H, m, Ar—H); LCMS retention time ˜3.43 min, m/z (FIANEG)241.9 [Cl³⁵(M)⁻, 100%] and 244.0 [Cl³⁷(M)⁻, 33%]. NMR and LCMS showedthat this material contained some starting material as a minor impuritybut no further purification was performed.

(ii) Thioacetic acid S-(2-oxo-1,2-dihydro-quinolin-6-yl) ester

To an ice bath cooled, stirred mixture of impure2-Oxo-1,2-dihydro-quinoline-6-sulfonyl chloride (20 g, ˜82 mmol), aceticacid (240 cm³) and acetic anhydride (80 cm³) was added sodium acetate(24 g) in three equal sized batches. Then Zinc (20 g) was added in smallbatches (exothermic reaction). After one hour the ice bath was removedand the reaction was left stirring at room temperature for five daysthen concentrated in vacuo then triturated with water (˜200 cm³). Thesolid that was formed was filtered off and dried in vacua to yieldThioacetic acid S-(2-oxo-1,2-dihydro-quinolin-6-yl) ester as a dry greysolid (11.7 g, ˜65%); δ_(H) (300 MHz; D6 DMSO) 2.42 (3H, s, COCH₃),6.51-6.57 (1H, m, Ar—H), 7.32-7.37 (1H, m, Ar—H), 7.43-7.48 (1H, m,Ar—H), 7.72 (1H, s, Ar—H), 7.88-7.92 (1H, m, Ar—H) and 11.95 (1H, br s,N—H); LCMS retention time ˜3.03 min, m/z (FIAPOS) 220 [(M+H)⁺, 100%].

(iii)EXO-6-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-1H-quinolin-2-one

To a stirred mixture of thioacetic acidS-(2-oxo-1,2-dihydro-quinolin-6-yl) ester (3.00 g, 13.7 mmol) andENDO-methanesulfonic acid 8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl ester(2.7 g, 12.3 mmol) with 2-propanol (˜150 cm³) was added pyrrolidine(1.14 cm³, 13.7 mmol) in one quick injection, at room temperature, undera flow of nitrogen gas causing a strong yellow colouration. The reactionwas then treated with potassium carbonate (2.1 g, 15.2 mmol) and thenheated to 80° C. The reaction was maintained at this temperatureovernight then cooled to room temperature and concentrated in vacuo to ayellow paste. This was treated with 1N HCl (100 cm³) and washed withCHCl₃ (3×50 cm³). The aqueous layer was filtered through paper and thenbasified using 2N NaOH (˜50 cm³), then extracted with CHCl₃ (3×50 cm³).The organics were dried (MgSO₄) and concentrated in vacuo then columnedon silica (gradient elution, 98:2 to 85:15, CH₂Cl₂:methanolic ammonia)but NMR still showed some minor impurities. The solid was recrystallizedby dissolving in the minimum warm (˜50° C.) EtOAc and methanol (1:1, ˜10cm³), then slowly cooling to room temperature, thus yieldingEXO-6-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-1H-quinolin-2-one(213 mg) as fine colourless crystals; δ_(H) (300 MHz; CDCl₃) 1.50-1.60(2H, m, 2× one of CH₂), 1.70-1.87 (4H, m, 4× one of CH₂), 1.98-2.06 (2H,m, 2× one of CH₂), 2.21 (3H, s, NCH₃), 3.10-3.27 (3H, m, HCS and 2×NCH),6.62-6.70 (1H, m, Ar—H), 7.20-7.27 (1H, m, Ar—H), 7.50-7.56 (1H, m,Ar—H), 7.62-7.64 (1H, m, Ar—H) and 7.70-7.73 (1H, m, Ar—H); LCMSretention time ˜2.03 min, m/z (FIAPOSES) 301.1 [(M+H)⁺, 100%].

EXAMPLE 45Exo-5-[(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)sulfanyl]-1,3-dihydro-2H-benzimidazol-2-one

By proceeding in a similar manner to Example 44 but using1,3-dihydro-2H-benzimidazol-2-one in place of 2-hydroxyquinoline therewas prepared the title compound as colourless solid. m.p.=178.5-181.6°C.

¹H nmr, δ_(H) (300 MHz; C₂D₆SO) 1.42-1.5 (2H, m, CH₂), 1.60-1.65 (4H,2×CH₂), 1.72-1.82 (2H, m, CH₂), 2.08-2.14 (3H, s, NCH₃), 3.00-3.05 (2H,m, NCHCH₂), 3.10-3.23 (1H, m, HCS), 6.87-6.89 (1H, m, Ar—H), 6.95-6.97(1H, s, Ar—H), 7.00-7.04 (1H, m, Ar—H), 10.60-10.68 (1H, s, NH),10.72-10.82 (1H, s, NH); LCMS retention time ˜0.803 min, m/z (FIAPOSES)290.1 [(M+H)⁺, 97.8%].

EXAMPLE 46Exo-6-[(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)sulfanyl]-2,4-(1H,3H)-quinazolindione

By proceeding in a similar manner to Example 44 but using2,4-(1H,3H)-quinazolindione in place of 2-hydroxyquinoline there wasprepared the title compound as colourless solid. m.p. >260° C.

¹H nmr, δ_(H) (300 MHz; C₂D₆SO) 1.60-1.78 (6H, m, 3×CH₂), 1.92-2.05 (2H,m, CH₂), 2.25-2.30 (3H, s, NCH₃), 3.28-3.48 (1H, m, HCS; 2H, m, NCHCH₂),7.10-7.15 (1H, m, Ar—H), 7.65-7.72 (1H, m, Ar—H), 7.83-7.88 (1H, s,Ar—H), 8.24-8.35 (1H, s, HCOOH), 10.90-11.90 (2H, s, 2×NH); LCMSretention time ˜0.910 min, m/z (FIAPOSES) 318.1 [(M+H)⁺, 97.4%].

EXAMPLE 47Exo-7-chloro-1-methyl-6-[(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)sulfanyl]-1,3-dihydro-2H-benzimidazole-2-thione

(i) 2,3-dichloro-N-methyl-6-nitroaniline

2,3-dichloro-6-nitroaniline (1.026 g, 5 mmole), was suspended in toluene(10 ml). To this vigorously stirred suspension was added 50% aqueoussodium hydroxide solution (1.7 g), tertiary-butyl ammonium chloride(0.07 g, 0.25 mmole) and dimethyl sulfate (0.51 ml, 5.4 mmole). After 4hr stirring at room temperature the intense red solution was washed withwater, brine, dried with magnesium sulfate, filtered, evaporated invacuo. Weight=1.03 g, m.p.=82° C.

Spectra: ¹H nmr, δ_(H) (300 MHz; CDCl₃) 2.96-3.05 (3H, d, N—CH₃),6.60-6.65 (1H, d, Ar—H; 1H, m, N—H), 7.72-7.80 (1H, d, Ar—H); LCMSretention time ˜5.959 min, m/z (GRADNL.M)=219.1 [(M−H)⁻, 100%].

(ii)Exo-2-chloro-N-methyl-3-[(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)sulfanyl]-6-nitroaniline

2,3-dichloro-N-methyl-6-nitroaniline (3.99 g, 18 mmole) and(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)ethanethioate (4.92 g, 24.7 mmole)were stirred in ethanol (90 ml). To this was added 2M aqueous sodiumhydroxide (25 ml, 50 mmole). The solution was stirred magnetically, atroom temperature, for 24 hr, under a nitrogen atmosphere. The mixturewas evaporated in vacuo, dissolved in chloroform, washed with water,then brine. The chloroform solution was extracted with 5M HCl, this waswashed with chloroform. The acid extract was basified with aqueous 50%sodium hydroxide, and extracted into chloroform, washed with brine,dried with magnesium sulfate, filtered, evaporated in vacuo, purified byflash chromatography, using 1% ammonia-methanol:dichloromethane (0% to10%). Weight=0.512 g of red oil, that crystallised on standing, m.p.=89°C.

Spectra: ¹H nmr, δ_(H) (300 MHz; CDCl₃) 1.64-1.72 (2H, m, CH₂),1.83-1.93 (4H, m, 2×CH₂), 2.08-2.14 (2H, m, CH₂), 2.30-2.34(3H, s,NCH₃), 3.11-3.14 (3H, d, NCH₃) 3.21-3.24 (2H, m, NCHCH₂),3.50-3.62 (1H,m, HCS), 6.62-6.65 (1H, d, Ar—H), 7.00-7.10 (1H, s, N—H), 7.90-7.92 (1H,d, Ar—H), LCMS retention time 1.930 min, m/z (GRADNL.M)=342.1 [(M−H)⁺,100%]

(iii)Exo-3-chloro-N²-methyl-4-[(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)sulfanyl]-benzenediamine

Exo-2-chloro-N-methyl-3-[(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)sulfanyl]-6-nitroaniline(0.512 g, 1.5 mmole) was dissolved in ethyl acetate (20 ml), and to thiswas added SnCl₄.2H₂O (1.69 g, 7.5 mmole). The stirred mixture wasbrought to reflux, under a nitrogen atmosphere, and held at thistemperature for 20 min. The supernatent liquid of the cooled solutionwas added to an acid ion-exchange solid phase contained in a cartridge(10 g, SCX-2). A gum that remained in the flask was repeatedly extractedinto ethyl acetate, and this was also added to the cartridge. Thecartridge was washed with ethyl acetate, then methanol. The product wasstripped off the cartridge using 2M NH₃ in methanol. The fractionscontaining product were combined, re-filtered to remove residual tinresidues, evaporated in vacuo. Weight of solid (broad m.p.),=0.471 g.Spectra: ¹H nmr, δ_(H) (300 MHz; CD₃OD) 1.92-2.95 (6H, m, 3×CH₂),2.22-2.34 (2H, m, CH₂), 2.65-2.70 (3H, s, NCH₃), 2.75-2.77 (3H, broadsinglet, NCH₃), 3.34-3.50 (1H, m, HCS), 3.85-3.92 (2H, m, NCHCH₂),6.64-6.70 (1H, d, Ar—H), 7.12-7.15 (1H, d, Ar—H), LCMS retention time˜1.223 min, m/z (GRADNL.M)=312.1 [(M−H)⁺, 100%]. Similarly preparedwere:Exo-3-chloro-N²-propyl-4-[(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)sulfanyl]-benzenediamine(an oil), m/z (GRADNL.M)=340.1, andExo-3-chloro-N²-isopropyl-4-[(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)sulfanyl]-benzenediamine(an oil),), m/z (GRADNL.M)=340.1

(iv)Exo-7-chloro-1-methyl-6-[(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)sulfanyl]-1,3-dihydro-2H-benzimidazole-2-thione

Exo-3-chloro-N²-methyl-4-[(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)sulfanyl]-benzenediamine(0.475 g, 1.52 mmole) was dissolved in THF (15 ml) and DMF (15 ml).Triethylamine (0.86 ml, 6.16 mmole) was added and the solution wascooled to 0° C. in an ice-water bath. Thiophosgene (0.134 ml, 1.76mmole) was dissolved in THF (10 ml) and added, with stirring, dropwise,to the solution of the benzendiamine, at such a rate that thetemperature did not exceed 10° C. On completion of addition the mixturewas stirred at ambient temperature for 1 hr. The mixture was evaporatedin vacuo, the residue was dissolved in water, if necessary using a fewdrops of acetic acid to aid solubilisation. This solution was added toan acid ion-exchange resin contained in a cartridge (10 g, SCX-2), thecartridge was washed through with water, then methanol. The productcould be stripped off using 2M-NH₃ in methanol. Fractions containingproduct were bulked, evaporated, and purified by flash chromatographyusing florisil as stationary phase and gradient elution withmethanol:chloroform (2% to 10%). Weight =0.0494 g, m.p.=217.3-219.1° C.

Spectra: ¹H nmr, δ_(H) (300 MHz; CDCl₃) 1.70-1.88 (2H, m, CH₂),1.92-1.98 (2H, m, CH₂), 2.06-2.35 (4H, m, 2×CH₂; 3H, s, NCH₃), 3.10-3.24(1H, m, HCS), 3.45-3.52 (2H, m, NCHCH₂), 4.10-4.14 (3H, s, NCH₃),6.50-6.52 (1H, s, Ar—H), 7.22-7.25 (1H, s, Ar—H), LCMS retention time˜2.603 min, m/z (FIAPOSES)=354.1 [(M+H)⁺, 98.6%].

EXAMPLE 48Exo-7-chloro-1-propyl-6-[(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)sulfanyl]-1,3-dihydro-2H-benzimidazole-2-thione

By proceeding in a similar manner to Example 47 there was prepared thetitle compound as colourless solid. m.p.=131.4-133.9° C.

¹H nmr, δ_(H) (300 MHz; CDCl₃) 1.00-1.06 (3H, m, CH₃), 1.08-1.22 (2H, m,CH₂), 1.70-2.12 (8H, m, 4×CH₂), 2.20-2.22 (3H, s, NCH₃), 3.14-3.25 (1H,m, HCS), 3.38-3.42 (2H, m, NCHCH₂), 4.52-4,58 (2H, m, CH₂), 6.70-6.72(1H, s, Ar—H), 7.25-7.30 (1H, s, N—H; 1H, s, Ar—H), LCMS retention time˜2.291 min, m/z (FIAPOSES) 382.1 [(M+H)⁺, 100%]

EXAMPLE 49Exo-7-chloro-1-isopropyl-6-[(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)sulfanyl]-1,3-dihydro-2H-benzimidazole-2-thione

By proceeding in a similar manner to Example 47 there was prepared thetitle compound as colourless solid. m.p.=228.9-230.9° C. Spectra: ¹Hnmr, δ_(H) (300 MHz; CDCl₃) 1.58-1.60 (6H, d, 2×CH₃), 1.72-2.08 (8H, m,4×CH₂), 2.28-2.30 (3H, s, NCH₃), 3.23-3.40 (2H, m, NCHCH₂H; 1H, m, HCS),5.48-5.60 (1H, m, C—H), 7.17-7.19 (1H, s, Ar—H), 7.42-7.48(1H, s, Ar—H),LCMS retention time ˜2.115 min, m/z (FIAPOSES)=382.1 [(M+H)⁺, 98.2%]

EXAMPLE 50Exo-7-chloro-1-methyl-6-[(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)sulfanyl]-1,3-dihydro-2H-benzimidazol-2-onehydrochloride

Exo-3-chloro-N²-methyl-4-[(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)sulfanyl]-benzenediamine[Example 46 (iii), 0.471 g, 1.51 mmole], was dissolved in a mixture ofTHF (20 ml) and DMF (20 ml). To this was added triethylamine (0.86 ml,6.16 mmole), and the mixture was cooled to 0° C. in an ice-water bath. A20% phosgene in toluene solution was added, dropwise, to this stirredsolution, at a rate that the temperature never exceeded 10° C. Thesolution was allowed to stir at ambient temperature for 1 hr, themixture was then evaporated in vacuo. The residue was dissolved in water(a few drops of acetic acid were added to facilitate solubilisation),and added to an acid ion-exchange polymer in a cartridge (10 g, SCX-2).The cartridge was washed with water, then methanol, the product wasstripped off using 2M NH₃ in methanol. Fractions containing product werebulked, evaporated, purified by flash chromatography, gradient elutionusing ammonia-methanol:dichloromethane (0% to 12.5%). Fractionscontaining product were bulked, dissolved in chloroform, and enoughethereal HCl was added such that the solution was acid by pH paper. Thesolution was evaporated to dryness, triturated with dry ether, filtered,dried. Weight=0.0879 g, m.p. >260° C. Spectra: ¹H nmr, □H (300 MHz;CD₃OD) 1.95-2.40 (8H, m, 4×CH₃), 2.70-2.80 (3H, s, NCH₃), 3.42-3.55 (1H,m, HCS), 3.72-3.75 (3H, s, NCH₃), 3.86-3.92 (2H, m, NCHCH₂H) 6.99-7.20(1H, s, Ar—H), 7.36-7.42 (1H, s, Ar—H), LCMS retention time 1.468 min,m/z (FIAPOSES)=338.1 [(M+H)⁺, 100%]

EXAMPLE 51Exo-5-chloro-1-methyl-6-[(8-methyl-8-azabicyclo[3.2.1]oct-3-yl)sulfanyl]-1,3-dihydro-2H-benzimidazol-2-one

By proceeding in a similar manner to examples 47 and 50 but using3,4-dichloro-N-methyl-6-nitroaniline there was prepared the titlecompound as a colourless solid. m.p.=206.4-207.2° C. ¹H nmr, δ_(H) (300MHz; CDCl₃) 1.63-1.73 (2H, m, CH₂), 1.90-1.96 (4H, 2×CH₂), 2.04-2.10(2H, m, CH₂), 2.10-2.14 (3H, s, NCH₃), 3.11-3.20 (1H, m, HCS), 3.12-3.25(2H, m, NCHCH₂), 3.25-3.35 (3H, s, NCH₃), 6.75-6.78 (1H, s, Ar—H),7.05-7.08 (1H, s, Ar—H), 12.05-12.95 (1H, s, NH); LCMS retention time1.966 min, m/z (FIAPOSES) 338.1 [(M+H)⁺, 100%].

EXAMPLE 52EXO-5-Chloro-6-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-3H-benzooxazol-2-onehydrochloride salt

(i) 5-Chloro-2-oxo-2,3-dihydro-benzooxazole-6-sulfonic acid

To a stirred mixture of chlorzoxazone (10 g, 58.9 mmol) and CH₂Cl₂ (˜500cm³) was added chlorosulphonic acid (4.3 cm³, 64.8 mmol) at roomtemperature. The reaction was left at room temperature for a weekwhereupon all the solvent had evaporated leaving a white solid. NMRshowed a 1:2 mixture of product and starting material respectively. Thiscrude was extracted with H₂O (3×15 cm³), then the aqueous wasconcentrated in vacuo to a sticky solid which was washed with CH₂Cl₂(4×40 cm³) to yield 5-Chloro-2-oxo-2,3-dihydro-benzooxazole-6-sulfonicacid as a fine white solid; δ_(H) (300 MHz; D6 DMSO) 7.10 (1H, s, Ar—H),7.68 (1H, s, Ar—H) and 11.80 (1H, s, N—H); LCMS retention time ˜0.47min, m/z (FIANEG) 247.9 [Cl³⁵ (M−H)⁻, 100%] and 249.9 [Cl³⁷ (M−H)⁻,33%].

(ii) 5-Chloro-2-oxo-2,3-dihydro-benzooxazole-6-sulfonyl chloride

To a stirred mixture of5-Chloro-2-oxo-2,3-dihydro-benzooxazole-6-sulfonic acid (˜10 g, 40 mmol)and CH₂Cl₂ was added thionyl chloride (5.8 cm³, 80 mmol) at roomtemperature, causing gas to be evolved. This was stirred at roomtemperature for two hours but the solid didn't dissolve and FIA onlyshowed starting material. Therefore a few drops of DMF were added andthe reaction heated to 50° C. overnight but no reaction occurred. Thestarting material was filtered off and then treated with neat thionylchloride (15 cm³) and heated to 70° C. overnight, FIA now detectedstarting material and product, so the reaction was treated with DMF (2×1cm³) to aid solvation, FIA showed completion of the reaction. Thereaction was diluted with CH₂Cl₂ (100 cm³) then poured onto ice. Thesolid formed was filtered off and dried in vacuo yielding 5-5Chloro-2-oxo-2,3-dihydro-benzooxazole-6-sulfonyl chloride (4.6 g, 43%)as a fine white solid; δ_(H) (300 MHz; D6 DMSO) 7.09 (1H, s, Ar—H), 7.69(1H, s, Ar—H) and 11.81 (1H, s, N—H); m/z (FIANEG) 266.0 [(M−H)⁻, 100%]and 268.0 [(M−H)⁻, 67%].

(iii) Thioacetic acidS-(3-acetyl-5-chloro-2-oxo-2,3-dihydro-benzooxazol-6-yl) ester

To an ice bath cooled stirred solution of5-Chloro-2-oxo-2,3-dihydro-benzooxazole-6-sulfonyl chloride (4.6 g, 17.2mmol) in acetic acid (60 cm³) and acetic anhydride (20 cm³) was addedsodium acetate (8 g). This mixture was treated with zinc (5×1 g) inbatches due to the strongly exothermic reaction. This was stirred atroom temperature overnight to give a pale grey slurry. The reaction wasconcentrated in vacuo then treated with H₂O. The solid was filtered offand washed with more H₂O then dried in vacuo to yield thioacetic acidS-(3-acetyl-5-chloro-2-oxo-2,3-dihydro-benzooxazol-6-yl) ester as a greysolid (4.4 g, 90%); δ_(H) (300 MHz; D6 DMSO) 2.48 (3H, s, COCH₃), 2.60(3H, s, COCH₃), 7.72 (1H, s, Ar—H) and 8.08 (1H, s, Ar—H); LCMSretention time ˜4.86 min.

(iv)EXO-5-Chloro-6-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-3H-benzooxazol-2-onehydrochloride salt

To a stirred mixture of thioacetic acidS-(3-acetyl-5-chloro-2-oxo-2,3-dihydro-benzooxazol-6-yl) ester (2.00 g,6.98 mmol), ENDO-methanesulfonic acid8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl ester (1.53 g, 6.98 mmol) andcesium fluoride (1.05 g, 6.98 mmol) in DMF was added pyrrolidine (1.17cm³, 14.0 mmol) in one quick injection, at 80° C., under a flow ofnitrogen gas. The reaction was maintained at this temperature overnightthen treated with acetic anhydride (1 cm³) and concentrated in vacuo toa sticky oil. This was purified using SCX powder to yield a thick brownoil which was triturated with CH₂Cl₂ and diethyl ether to yield a veryinsoluble powder. This powder was stirred for two days in 0.5NHCl_((aq)) and then treated with methanol. Not all of the solid woulddissolve so the mother liquor was filtered and concentrated in vacuo toyieldEXO-5-Chloro-6-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-3H-benzooxazol-2-onehydrochloride salt (48 mg) as a pale yellow solid; δ_(H) (300 MHz; D4methanol) 1.81-2.27 (8H, m, 4×CH₂), 2.62 (3H, s, NCH₃), 3.41-3.59 (1H,m, HCS), 3.75-3.85 (2H, m, 2×NCH), 7.25 (1H, s, Ar—H) and 7.43 (1H, s,Ar—H); LCMS retention time ˜2.10 min, m/z (FIAPOSES) 325.0 [Cl³⁵ (M+H)⁺,100%] and 327.0 [Cl³⁷ (M+H)⁺, 33%].

EXAMPLE 53EXO-7-Chloro-6-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-3H-benzooxazol-2-onehydrochloride salt

(i) 2-Chloro-3-fluoro-6-nitro-phenol

2-Chloro-3-fluoro-6-nitro-phenol (3 g, 15.7 mmol) was prepared using aliterature procedure from 2-Chloro-1,3-difluoro-4-nitro-benzene.(Hayakawa, Isao; Hiramitsu, Tokiyuki; Tanaka, Yoshiaki; Chem. Pharm.Bull.; 32; 12; 1984; 4907-4913);

(ii)EXO-2-Chloro-3-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-6-nitro-phenol

To a stirred solution of 2-Chloro-3-difluoro-6-nitro-phenol (3 g, 15.7mmol) and EXO-Thioacetic acid S-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl)ester (4.8 g, 24.1 mmol) in ethanol (100 cm³) was added 2N NaOH (2×12cm³) at room temperature under a flow of nitrogen gas. The reaction wasstirred at room temperature overnight then concentrated in vacuo,diluted with H₂O (50 cm³) then treated with 2N HCl causing rapidformation of solid. This solid was washed with 2N HCl_((aq)), CHCl₃ andmethanol to yieldEXO-2-Chloro-3-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-6-nitro-phenol(966 mg, 19%) as a fine yellow solid; δ_(H) (300 MHz; D6 DMSO) 2.09-2.34(8H, m, 4×CH₂), 2.50 (3H, s, NCH₃), 3.80-4.03 (3H, m, SCH and 2×NCH),7.15-7.29 (1H, m, Ar—H) and 7.88-7.99 (1H, m, Ar—H); LCMC retention˜2.75 min, m/z (FIAPOS) 329.1 [Cl³⁵ (M+H)⁺, 100%] and 331.0 [Cl³⁷(M+H)⁺, 33%].

(iii)EXO-6-Amino-2-chloro-3-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-phenolhydrochloride salt

A slurry ofEXO-2-Chloro-3-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-6-nitro-phenol(1.67 g, 5.1 mmol) in methanol was treated with ethanolic HCl and thenwater to try to aid solvation but solid still remained. His mixture wasadded to a cooled slurry of 5% Pd/C (400 mg) with ethanol. This mixturewas placed under a pressurised atmosphere of hydrogen gas (60 PSI) atroom temperature for one hour. The organic solid had dissolved leavingthe undissolved palladium on charcoal. The reaction was filtered throughcelite® then concentrated in vacuo to yieldEXO-6-Amino-2-chloro-3-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-phenolhydrochloride salt (1.55 g, 91%) as a white crystalline solid; δ_(H)(300 MHz; D4 methanol) 2.10-2.51 (8H, m, 4×CH₂), 2.79 (3H, s, NCH₃),3.79-3.92 (1H, m, SCH), 4.02-4.10 (2H,m, 2×NCH), 7.25-7.32 (1H, m, Ar—H)and 7.37-7.43 (1H, m, Ar—H); LCMC retention ˜0.92 min, m/z (FIAPOS)150.1 [Cl³⁵ (M+2H)²⁺, 90%], 151.1 [Cl³⁷ (M+2H)²⁺, 30%], 299.1[Cl³⁵(M+H)⁺, 100%] and 301.1 [Cl³⁷ (M+H)⁺, 33%].

(iv)EXO-7-Chloro-6-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-3H-benzooxazol-2-onehydrochloride salt

To a stirred solutionEXO-6-Amino-2-chloro-3-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-phenolhydrochloride salt (506 mg, 1.7 mmol) and triethylamine (684 mg, 6.8mmol) in CHCl₃ (30 cm³) was added a solution of triphosgene (167 mg,0.56 mmol) as a solution in CHCl₃ (3×2 cm³) causing an exothermicreaction. The reaction was concentrated in vacuo to a greyish brownsolid which was washed with methanol (3×10 cm³) to yield a brownsolution and a sticky grey paste. The solid was dried in vacuo overnightthen dissolved in a mixture of methanol (100 cm³) and CHCl₃ (5 cm³) andtreated with a few drops of ethanolic HCl solution. This solution wasconcentrated in vacuo to yieldEXO-7-Chloro-6-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-3H-benzooxazol-2-onehydrochloride salt (160 mg) as a fluffy white solid; δ_(H) (300 MHz; D4methanol) 1.82-2.26 (8H, m, 4×CH₂), 2.65 (3H, s, NCH₃), 3.35-3.49 (1H,m, HCS), 3.72-3.83 (2H, m, 2×NCH), 6.90-7.01 (1H, m, Ar—H) and 7.39-7.46(1H, m, Ar—H); LCMS retention time ˜2.62 min, m/z (FIAPOSES) 325.0 [Cl³⁵(M+H)⁺, 100%] and 327.0 [Cl³⁷ (M+H)⁺, 33%].

EXAMPLE 54EXO-7-Chloro-6-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-3H-benzooxazole-2-thione

To a stirred solutionEXO-6-Amino-2-chloro-3-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-phenolhydrochloride salt (Example 16 (iii), 250 mg, 0.84 mmol) andtriethylamine (338 mg, 3.4 mmol) in CHCl₃ (30 cm³) was added a solutionof thiophosgene (115 mg, 1.00 mmol) as a solution in CHCl₃ (3 cm³).After stirring at room temperature for one hour the reaction was loadedonto a 10 g SCX-2 cartridge, washed with methanol then extracted usingmethanolic ammonia (˜2N). The basic eluant was concentrated in vacuo toa brown solid which was washed with CHCl₃ (2×5 cm³) and methanol (2×2cm³) to yieldEXO-7-Chloro-6-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-3H-benzooxazole-2-thione(136 mg, 48%) as a pale brown solid; δ_(H) (300 MHz; D6 DMSO) 1.79-1.99(6H, m, 6× one of CH₂), 2.14-2.19 (2H, m, 2× one of CH₂), 2.53 (3H, s,NCH₃), 3.28-3.50 (1H, m, HCS), 3.72-3.86 (2H, m, 2×NCH), 6.92-7.0 (1H,m, Ar—H) and 7.20-7.28 (1H, m, Ar—H); LCMS retention time ˜2.83 min, m/z(FIAPOSES) 341.0 [Cl³⁵ (M+H)⁺, 100%] and 343.0 [Cl³⁷ (M+H)⁺, 33%].

EXAMPLE 55EXO-5-Chloro-3-methyl-6-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-1H-quinazoline-2,4-dione

By proceeding in a similar manner to Example 41 but usingN-methyl-2,3-dichlorobenzene-carboxamide in step (i) and omitting step(iv), there was prepared the title compound as a colourless solid. δ_(H)(300 MHz; CDCl₃) 1.52-1.61 (2H, m, 2× one of CH₂), 1.69-1.91 (4H, m,4×one of CH₂), 1.99-2.09 (2H, m, 2× one of CH₂), 2.25 (3H, s, CHNCH₃),3.17-3.22 (2H, m, 2×NCH), 3.30-3.49 (4H, m, CONCH₃ and SCH), 7.84-6.92(1H, m, Ar—H) and 7.61-7.70 (1H, m, Ar—H); LCMS retention time ˜1.37min, m/z (FIAPOSES) 366.1 [Cl³⁵ (M+H)⁺, 100%] and 368.1 [Cl³⁷ (M+H)⁺,33%].

EXAMPLE 56EXO-4-Chloro-5-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-1H-indazole

(i) 1,2-Dichloro-3-methyl-4-nitro-benzene

The title compound was prepared according to the procedure described inpatent application EP 0778 258 A2 (Example 1). The crude mixture ofproducts and starting material was purified using Flash Chromatographyon silica (eluant=hexane). Yielding a 10:1 mixture of1,2-Dichloro-3-methyl-4-nitro-benzene {δ_(H) (300 MHz; CDCl₃) 7.41-7.50(1H, m, Ar—H) and 7.65-7.71 (1H, m, Ar—H); LCMC retention ˜6.42 min} and2,3-Dichloro-1-methyl-4-nitro-benzene {δ_(H) (300 MHz; CDCl₃) 8.01-8.08(1H, m, Ar—H) and 8.17-8.21 (1H, m, Ar—H); LCMC retention ˜6.57 min} asa waxy solid.

(ii)EXO-3-(2-Chloro-3-methyl-4-nitro-phenylsulfanyl)-8-methyl-8-aza-bicyclo[3.2.1]octane

To a stirred solution of 1,2-Dichloro-3-methyl-4-nitro-benzene (300 mg,1.45 mmol) and EXO-Thioacetic acidS-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl) ester (376 mg, 1.89 mmol) inethanol was added 2N NaOH (˜2 cm³) at room temperature under a flow ofnitrogen gas. The reaction was stirred at room temperature overnightthen treated with 2N HCl (2 cm³) to reach pH-5 then concentrated invacuo onto silica and columned using gradient elution (98:2 to 85:15CH₂Cl₂:methanolic ammonia) yieldingEXO-3-(2-Chloro-3-methyl-4-nitro-phenylsulfanyl)-8-methyl-8-aza-bicyclo[3.2.1]octane(˜150 mg) as a crystalline solid; δ_(H) (300 MHz; CDCl₃) 1.62-1.71 (2H,m, 2× one of CH₂), 1.87-1.97 (4H, m, 4× one of CH₂), 2.09-2.19 (2H, m,2× one of CH₂), 2.31 (3H, s, CH₃), 2.60 (3H, s, CH₃), 3.21-3.28 (2H, m,2×NCH), 3.50-3.61 (1H, m SCH), 7.12-7.20 (1H, m, Ar—H) and 7.70-7.79(1H, m, Ar—H); LCMC retention 3.56 min, m/z (FIAPOS) 327.1 [Cl³⁵ (M+H)⁺,100%] and 329.1 [Cl³⁷ (M+H)⁺, 33%].

(iii)EXO-3-Chloro-2-methyl-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-phenylamine

To a slurry of 5% Pd on charcoal (145 mg) and ethanol was added asolution ofEXO-3-(2-Chloro-3-methyl-4-nitro-phenylsulfanyl)-8-methyl-8-aza-bicyclo[3.2.1]octane(145 mg, 0.44 mmol) in ethanol. This mixture was placed under apressurised atmosphere of hydrogen gas (60 PSI) at room temperature for90 minutes. The reaction was filtered through celite®(D thenconcentrated in vacuo to yieldEXO-3-Chloro-2-methyl-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-phenylamine(77 mg); δ_(H) (300 MHz; CDCl₃) 1.50-1.59 (2H, m, 2× one of CH₂),1.60-1.71 (2H, m, 2× one of CH₂), 1.73-189 (2H, m, 2× one of CH₂),1.93-2.01 (2H, m, 2× one of CH₂), 2.24 (3H, s, CH₃), 2.30 (3H, s, CH₃),3.14-3.31 (3H, m, SCH and 2×NCH), 6.47-6.54 (1H, m, Ar—H) and 7.16-7.22(1H, m, Ar—H);

(iv)EXO-4-Chloro-5-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-1H-indazole

To a stirred solutionEXO-3-Chloro-2-methyl-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-phenylamine(1.1 g, 3.7 mmol) in HBF_(4(aq)) (48% solution in H₂O) (2.5 cm³) wasadded NaNO₂ (256 mg, 3.7 mmol) as a solution in H₂O at room temperature.The reaction changed colour from orange/yellow to blue/green. After onehour the reaction was filtered to yield a sticky pale green solid whichwas washed with water then CHCl₃ and then dried in vacuo. This solid wastreated with CHCl₃ and 18-crown-6 ether (catalytic amount) and thenPotassium acetate (727 mg, 7.4 mmol) was added causing a colour changefrom green to reddish orange with a sticky insoluble gum. The solutionwas purified using Flash chromatography {gradient elution (98:2 to 85:15CH₂Cl₂:methanolic ammonia)} yieldingEXO-4-Chloro-5-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-1H-indazole(510 mg) as a reddish brown dry foam; δ_(H) (300 MHz; CDCl₃) 1.56-1.70(2H, m, 2× one of CH₂), 1.72-2.10 (6H, m, 6× one of CH₂), 2.22 (3H, s,NCH₃), 3.18-3.40 (3H, m, HCS and 2×NCH), 7.11-7.20 (1H, m, Ar—H),7.41-7.50 (1H, m, Ar—H) and 8.08 (1H, s, Ar—H); LCMS retention time˜2.38 min, m/z (FIAPOSES) 308.1 [Cl³⁵ (M+H)⁺, 100%] and 310.1 [Cl³⁷(M+H)⁺, 33%].

EXAMPLE 57EXO-4-Chloro-5-(8-methyl-8-aza-bicyclo[3.2.1]octane-3-sulfonyl)-1H-indazole

To a cloudy slurry ofEXO-4-Chloro-5-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-1H-indazole(Example 19, 393 mg, 1.28 mmol) in methanol (18 cm³) with a small amountof CHCl₃ (2 cm³) to try and aid solvation, was added a solution of Oxone(1.57 g, 2.56 mmol) at room temperature causing instant formation of awhite solid. After stirring for one hour the reaction was loaded onto aSCX-2 cartridge and washed with methanol, then the cartridge wasextracted with methanolic ammonia (˜2N). The basic solution wasconcentrated in vacua to yieldEXO-4-Chloro-5-(8-methyl-8-aza-bicyclo[3.2.1]octane-3-sulfonyl)-1H-indazole(420 mg) as a brown foam; δ_(H) (300 MHz CDCl₃) 1.51-1.71 (4H, m, 4× oneof CH₂), 2.02-2.19 (4H, m, 4× one of CH₂), 2.31 (3H, s, NCH₃), 3.29-3.35(2H, m, 2×NCH), 3.71-3.89 (1H, m, HCS), 7.40-7.48 (1H, m, Ar—H),7.90-7.99 (1H, m, Ar—H) and 8.25 (1H, s, Ar—H); LCMS retention time˜1.69 min, (FIAPOSES) 340.0 [Cl³⁵ (M+H)⁺, 100%], 342.0 [Cl³⁷ (M+H)⁺,33%].

By proceeding in a similar manner there were prepared the following:

EXAMPLE 58 EXO5,7-Dichloro-6-(8-methyl-8-aza-bicyclo[3.2.1]octane-3-sulfonyl)-1H-quinolin-2-one

δ_(H) (300 MHz; D4 methanol) 1.78-1.99 (4H, m, 4× one of CH₂), 2.28-2.49(4H, m, 4× one of CH₂), 2.53 (3H, s, NCH₃), 4.10-4.25 (1H, m, HCS),6.99-7.08 (1H, m, Ar—H), 8.11 (1H, s, Ar—H) and 8.61-8.69 (1H, m, Ar—H);LCMS retention time 0.64 m in, m/z (FIAPOSES). 401.0 [Cl³⁵+Cl³⁵ (M+H)⁺,100%] and 403.0 [Cl³⁵+Cl³⁷ (M+H)⁺, 67%].

EXAMPLE 59EXO-5-Chloro-6-(8-methyl-8-aza-bicyclo[3.2.1]octane-3-sulfonyl)-3H-benzooxazol-2-one

δ_(H) (300 MHz; D6 DMSO) 1.45-1.59 (4H, m, 4× one of CH₂), 1.80-2.00(4H, m, 4× one of CH₂), 2.26 (3H, s, NCH₃), 3.64-3.79 (1H, m, SCH), 6.92(1H, s, Ar—H) and 7.28 (1H, s, Ar—H);

EXAMPLE 60EXO-6-(8-Methyl-8-aza-bicyclo[3.2.1]octane-3-sulfonyl)-1H-quinolin-2-one

δ_(H) (300 MHz; D4 Methanol) 1.69-1.89 (4H, m, 4× one of CH₂), 2.00-2.20(4H, m, 4× one of CH₂), 2.40 (3H, s, NCH₃), 3.45-3.55 (2H, m, 2×NCH),3.56-3.67 (1H, m, HCS), 6.71-6.79 (1H, m, Ar—H), 7.51-7.58 (1H, m,Ar—H), 7.95-8.02 (1H, m, Ar—H), 8.08-8.13 (1H, m, Ar—H) and 8.22-8.24(1H, m, Ar—H).

EXAMPLE 61 EXO6-(8-Methyl-8-aza-bicyclo[3.2.1]octane-3-sulfonyl)-3H-benzooxazol-2-one

δ_(H) (300 MHz; D6 DMSO) 1.50-1.63 (4H, m, 4× one of CH₂), 1.72-1.85(2H, m, 2× one of CH₂), 1.88-1.99 (2H, m, 2× one of CH₂), 2.22 (3H, s,NCH₃), 3.29-3.39 (2H, m, 2×NCH), 7.11-7.20 (1H, m, Ar—H) and 7.47-7.58(2H, m, 2×Ar—H); LCMS retention time ˜0.95 min, m/z (FIAPOS) 323.1[(M+H)⁺, 100%].

EXAMPLE 62EXO-7-Chloro-6-(8-methyl-8-aza-bicyclo[3.2.1]octane-3-sulfonyl)-3H-benzooxazol-2-onehydrochloride salt

EXO-7-Chloro-6-(8-methyl-8-aza-bicyclo[3.2.1]octane-3-sulfonyl)-3H-benzooxazol-2-onehydrochloride salt; δ_(H) (300 MHz; D4 methanol) 1.81-1.99 (4H, m, 4×one of CH₂), 2.10-2.30 (4H, m, 4× one of CH₂), 2.61 (3H, s, NCH₃),3.74-4.00 (3H, m, HCS and 2×NCH), 7.22-7.36 (1H, m, Ar—H) and 7.70-7.80(1H, m, Ar—H).

EXAMPLE 63EXO-3-Methyl-6-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfonyl)-1H,3H,4H-tetrahydroquinazolin-2-one

EXAMPLE 64EXO-6-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-3H-benzooxazol-2-one

By proceeding in a similar manner to Example 44 but using3H-benzooxazol-2-one in place of 2-hydroxyquinoline, there was preparedthe title compound as a colourless solid.

EXAMPLE 65 EXO-6-(8-Methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-1H,3H,4H-tetrahydroquinolin-2-one

By proceeding in a similar manner to Example 43 but using1H,3H,4H-tetrahydroquinolin-2-one in place of 2-hydroxyquinoline, therewas prepared the title compound as a pale yellow solid.

EXAMPLE 66EXO-3-Methyl-6-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-1H,3H,4H-tetrahydroquinazolin-2-one

By proceeding in a similar manner to Example 44 but using3-methyl-1H,3H,4H-tetrahydroquinazolin-2-one in place of2-hydroxyquinoline, there was prepared the title compound as a paleyellow solid.

EXAMPLE 67 (a)EXO-5,7-Dichloro-6-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-1H-quinolin-2-one

(i)EXO-3-(2,6-Dichloro-4-nitro-phenylsulfanyl)-8-methyl-8-aza-bicyclo[3.2.1]octane

To a pale brown solution of EXO-Thioacetic acidS-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl) ester (3.93 g, 19.7 mmol) and1,2,3-Trichloro-5-nitro-benzene (5.37 g, 23.7 mmol) in ethanol was added2 NaOH (10.85 cm³, 21.7 mmol) at room temperature. After about fiveminutes the reaction was neutralised using 2N HCl (˜1 cm³) thenconcentrated in vacuo to remove the ethanol. The aqueous was treatedwith 2N NaOH (1.5 cm³) and extracted using CHCl₃ (2×100 cm³), theorganics were combined, dried (MgSO₄) and concentrated in vacuo to darkyellow oil. This oil was purified by Flash Chromatography on silica(95:5 to 85:15; CH₂Cl₂, methanolic ammonia) yieldingEXO-3-(2,6-Dichloro-4-nitro-phenylsulfanyl)-8-methyl-8-aza-bicyclo[3.2.1]octane(5.12 g, 83%) as long yellow crystals {δ_(H) (300 MHz; CDCl₃) 1.47-1.70(4H, m, 4× one of CH₂), 1.87-2.05 (4H, m, 4× one of CH₂), 2.30 (3H, s,NCH₃), 3.11-3.20 (2H, m, 2×NCH), 3.60-3.73 (1H, m SCH) and 8.23 (2H, m,2×Ar—H).

(ii)EXO-3,5-Dichloro-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-phenylamine

To a slurry of 5% Pd on charcoal (2 g) and ethanol was added a solutionofEXO-3-(2,6-Dichloro-4-nitro-phenylsulfanyl)-8-methyl-8-aza-bicyclo[3.2.1]octane(5.12 g, 14.8 mmol) in ethanol. This mixture was placed under apressurised atmosphere of hydrogen gas (60 PSI) at room temperatureovernight. The reaction was filtered through celite® then concentratedin vacuo to give a colourless oil which was triturated with diethylether then concentrated in vacuo to yieldEXO-3,5-Dichloro-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-phenylamine(4.33 g, 93%) as a dry white foam; δ_(H) (300 MHz; CDCl₃); 1.47-1.70(4H, m, 4× one of CH₂), 1.82-2.03 (4H, m, 4× one of CH₂), 2.29 (3H, s,NCH₃), 3.11-3.21 (2H, m, 2×NCH), 3.22-3.39 (1H, m SCH), 3.81-3.92 (NH₂)and 6.70 (2H, s, 2×Ar—H); LCMC retention ˜1.70 min, m/z (FIAPOS) 317.1[Cl³⁵+Cl³⁵ (M+H)⁺, 100%] and 319.1 [Cl³⁵+Cl³⁷ (M+H)⁺, 66%].

(iii)EXO-N-[3,5-Dichloro-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-phenyl]-3-ethoxy-acrylamide

To a solution ofEXO-3,5-Dichloro-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-phenylamine(300 mg, 0.95 mmol) in pyridine (1 cm³) and CH₂Cl₂ (10 cm³) was added3-Ethoxy-acryloyl chloride (127 mg, 0.95 mmol) which was synthesisedfrom ethoxy-ethene according to a literature procedure (Fernandez,Franco; Garcia-Mera, Xerardo; Morales, Melvin; Rodriguez-Borges, JoseE.; Synthesis; 2; 2001; 239-242). The reaction was stirred at roomtemperature for 2.5 hours then the solid that had formed was filteredoff and washed with CH₂Cl₂ to yieldEXO-N-[3,5-Dichloro-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-phenyl]-3-ethoxy-acrylamidehydrochloride salt (289 mg, ˜68%); δ_(H) (300 MHz; D4 methaol) 1.30-1.41(3H, m, OCH₂CH₃), 1.90-2.18 (6H, m, 6× one of CH₂), 2.23-2.47 (2H, m, 2×one of CH₂), 2.76 (3H, s, NCH₃), 3.48-3.52 (1H, m, SCH), 3.81-3.90 (2H,m, 2×NCH), 3.92-4.01 (2H, m, OCH₂CH₃), 5.55-5.65 (2H, m, NH and C═CH),7.59-7.69 (1H, m, C═CH) and 7.81-7.86 (2H, m, 2×Ar—H); LCMC retention˜2.38 min, m/z (FIAPOS) 415.1 [Cl³⁵+Cl³⁵ (M+H)⁺, 100%] and 417.1[Cl³⁵+Cl³⁷ (M+H)⁺, 66%].

(iv)EXO-5,7-Dichloro-6-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-1H-quinolin-2-onehydrochloride salt

EXO-N-[3,5-Dichloro-4-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-phenyl]-3-ethoxy-acrylamidehydrochloride salt (280 mg) was treated with concentrated H₂SO₄ (˜1 cm³)causing a colour change from yellow to red. After 10 minutes thereaction was poured onto crushed ice.

This was slowly warmed to room temperature to give a yellow solutionwhich was basified using 2N NaOH (˜10 cm³) to give a turbid mixturewhich was extracted with CHCl₃ (2×30 cm³). The chloroform layer wastreated with methanol, dried (MgSO₄) and concentrated in vacuo to ayellow solid. This yellow solid was washed with CH₂Cl₂ then dissolved inmethanol and treated with methanolic HCl to yieldEXO-5,7-Dichloro-6-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-1H-quinolin-2-onehydrochloride salt (100 mg) as a white solid; δ_(H) (300 MHz; CDCl₃)1.95-2.36 (8H, m, 4×CH₂), 2.78 (3H, s, NCH₃), 3.53-3.70 (1H, m, HCS),3.89-3.99 (2H, m, 2×NCH), 6.71-6.79 (1H, m, Ar—H), 7.52 (1H, s, Ar—H)and 8.28-8.33 (1H, m, Ar—H); LCMS retention time 1.65 min, m/z(FIAPOSES) 369.1 [Cl³⁵+Cl³⁵ (M+H)⁺, 100%] and 371.1 [Cl³⁵+Cl³⁷ (M+H)⁺,67%].

(b)EXO-5-chloro-8-methyl-6-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-1H-quinolin-2-one

By proceeding in a similar manner to Example 67(a) but using4,5-dichloro-2-nitro-toluene in step (i), there was preparedEXO-5-chloro-8-methyl-6-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-1H-quinolin-2-one.

(c)EXO-5,7-dichloro-6-(8-methyl-8-aza-bicyclo[3.2.1]oct-6-en-3-ylsulfanyl)-1H-quinolin-2-one

By proceeding in a similar manner to Example 67(a) but usingexo-thioacetic acid S-(8-methyl-8-aza-bicyclo[3.2.1]oct-6-en-3-yl) ester[Example 42(ii)] in step (i), there was preparedEXO-5,7-dichloro-6-(8-methyl-8-aza-bicyclo[3.2.1]oct-6-en-3-ylsulfanyl)-1H-quinolin-2-one.

EXAMPLE 68EXO-5,7-Dimethyl-6-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-1H-quinolin-2-one

By proceeding in a similar manner to Example 67 but using1-chloro-2,6-dimethyl-4-nitro-benzene in place of1,2,3-trichloro-5-nitro-benzene, there was prepared the title compoundas a colourless solid.

δ_(H) (300 MHz CDCl₃) 1.39-1.48 (2H, m, 2× one of CH₂), 1.54-1.63 (2H,m, 2× one of CH₂), 1.79-2.00 (4H, m, 4× one of CH₂), 2.25 (3H, s, NCH₃),2.61 (CH₃), 2.82 (CH₃), 2.91-3.08 (1H, m, HCS), 3.09-3.16 (2H, m,2×NCH), 6.65-6.71 (1H, m, Ar—H), 7.20 (1H, s, Ar—H), 7.97-8.05 (1H, m,Ar—H) and 12.32 (1H, br s, NH); LCMS retention time ˜2.93 min,(FIAPOSES). 329.1 [(M+H)⁺, 100%].

EXAMPLE 69 EXO5,7-Dichloro-6-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-1H-quinoline-2-thione

A slurryEXO-5,7-Dichloro-6-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-1H-quinolin-2-one(407 mg, 1.1 mmol) and Lawesson's Reagent[2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfide](446 mg, 1.10 mmol) in toluene was heated to reflux under a flow ofnitrogen gas overnight. The reaction was cooled to room temperature thenconcentrated in vacuo onto silica and columned using gradient elution(98:2 to 75:25 CH₂Cl₂:methanolic ammonia) yieldingEXO-5,7-Dichloro-6-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-1H-quinoline-2-thione(160 mg) as a bright yellow solid; δ_(H) (300 MHz CDCl₃) 1.47-1.55 (2H,m, 2× one of CH₂), 1.60-1.71 (2H, m, 2× one of CH₂), 1.89-2.01 (4H, m,4× one of CH₂), 2.29 (3H, s, NCH₃), 3.13-3.21 (2H, m, 2×NCH), 3.38-3.41(1H, m, HCS), 7.39-7.47 (2H, m, 2×Ar—H) and 7.91-7.99 (1H, m, Ar—H).

EXAMPLE 70EXO-7-Methyl-6-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-3H-benzooxazol-2-one

(i) 7-Methyl-3H-benzooxazol-2-one-6-sulfonic acid

7-Methyl-3H-benzooxazol-2-one [5,0 g, 33 mmol, prepared according to theprocedure described in J. Org. Chem. (1982), 47(14), 2804-6] was treatedwith chlorosulphonic acid as described in Example 15 (i) to give thetitle compound as an off-white solid (4.5 g, 60%). δ_(H) (300 MHz, DMSO)2.50 (s, 3H), 6.83 (d, 1H), 7.58 (d, 1H), 11.60 (brs, 1H)

(ii)EXO-7-Methyl-6-(8-methyl-8-aza-bicyclo[3.2.1]oct-3-ylsulfanyl)-3H-benzooxazol-2-one

A mixture of 7-methyl-3H-benzooxazol-2-one-6-sulfonic acid (2.5 g, 11mmol), triphenylphosphine (13 g, 50 mmol) and benzene (100 mL) washeated at reflux for 2 h under Dean and Stark conditions. The reactionwas cooled and treated with iodine (5 g, 20 mmol) in small portions. Thereaction was heated to reflux for a further 48 h before being cooled andwashed with 2.0M aqueous sodium hydroxide (2×20 ml). The combinedaqueous extracts were washed with chloroform (2×50 ml) and acidified topH 4 with concentrated hydrochloric acid. The resultant solid wascollected and dried to yield a white solid which was used directly inthe next step.

This material was treated with ENDO-methanesulfonic acid8-methyl-8-aza-bicyclo[3.2.1]oct-3-yl ester and cesium fluoride in DMFaccording to the procedure described in Example 15 (iii). There was thusobtained the title compound as a colourless solid.

δ_(H) (300 MHz; D4 methanol) 1.82-2.26 (8H), 2.65 (3H, s), 2.78 (3H, s),3.35-3.49 (1H, m), 3.72-3.83 (2H, m), 6.96 (1H, d) and 7.40 (1H, d).FIA-MS: 305 [(M+H)⁺, 100%].

EXAMPLE 71 6-(9-Methyl-9-aza-bicyclo[3.3.1]non-3(exo)-ylsulfanyl)-1-NH-quinolin-2-one

(i) 9-Methyl-9-aza-bicyclo[3,3,1]nonan-3(endo)-ol

To a −78° C. cooled solution of pseudopelletierine (771 mg, 5.04 mmol),obtained from the its chloro hydrate (pseudopelletierine chloride,commercially available) by treatment with saturated aqueous solution ofNaHCO₃, extracted with methylene chloride, and dried; in THF anhydrous(20 mL), a solution 1.0 M of DIBAL-H in hexane or toluene (10.8 mL, 10.8mmol) was added dropwise under N₂. The mixture was stirred and allowedto reach rt. for 3 h. The reaction was quenched with water (2 mL) andpoured into diethyl ether (60 mL). NaHCO₃ anhydrous (20 g) and Na₂SO₄anhydrous (20 g) were added. The mixture was stirred for 2 h at rt., andthen, it was filtered and the filtrate was evaporated. The residue wasthe title compound pure, 684 mg, 88%.

Ion Electrospray Mass Spectrum M+1: 156.

¹H NMR (200 MHz, CDCl₃) δ (ppm): 4.16 (m, 1H), 2.95 (br m, 2H),2.40-2.20 (m, 2H), 2.00-1.80 (m, 3H), 1.40-1.25 (m, 3H), 1.20-1.05 (in,2H)

¹³C NMR (50 MHz, CDCl₃) δ (ppm): 62.9, 51.6, 40.4, 34.8, 24.9, 14.4

(ii) 3(endo)-Hydroxy-9-aza-bicyclo[3,3,1]nonane-9-carboxylic acid ethylester

To a solution of the intermediate from step (i) (2.31 g, 14.90 mmol) indry chloroform (300 mL), ethyl chloroformate (9.97 mL, 104.30 mmol)followed by potassium bicarbonate (1.78 g, 17.88 mmol) were added. Themixture was heated at 80° C. and stirred under N₂ overnight. Thereaction was cooled down, quenched with water (30 mL) and extracted withchloroform. The organic layer was dried on MgSO₄ anhydrous, and thesolvent was removed in vacuo. The residue was the title compound pure,3.04 g, 96%. The product is a mixture of rotamers, the major one isdescribed as following:

Ion Electrospray Mass Spectrum M+1: 214

¹H NMR (200 MHz, CDCl₃) δ (ppm): 4.45 (br d, 2H), 4.10 (q, J=7.0 Hz,2H), 3.68 (m, 1H), 2.30 (m, 2H), 1.84 (br, s, 1H), 1.50-1.30 (m, 7H),1.23 (t, J=7.0 Hz, 3H)

¹³C NMR (75 MHz, CDCl₃) δ (ppm): 154.2, 62.8, 60.1, 43.9, 33.5, 29.3,13.7, 13.0

(iii) 3(endo)-Methanesulfonyloxy-9-aza-bicyclo[3,3,1]nonane-9-carboxylicacid ethyl ester

To an ice-cooled solution of the intermediate from step (ii) (3.04 g,14.27 mmol) in methylene chloride anhydrous, pyridine anhydrous (1.04mL, 12.84 mmol) followed by methanesulfonate chloride (1.21 mL, 15.70mmol) were added under N₂. The mixture was stirred overnight and allowedto reach rt. As the reaction hadn't finished pyridine anhydrous (2.08mL, 26 mmol) and methanesulfonate chloride (2.42 mL, 31.40 mmol) wereadded at 0° C. under N₂ The new mixture was stirred at rt for 24 h. Thereaction was quenched with an aqueous solution of NH₄OH (32%), andextracted with methylene chloride. The organic layer was washed withbrine and dried on MgSO₄ anh. The solvent was removed in vacuo to givethe title compound, 1.34 g, 32%. The product is a mixture of rotamers,the major one is described as following

Ion Electrospray Mass Spectrum M+1: 292

¹H NMR (200 MHz, CDCl₃) δ (ppm): 4.66 (m, 1H), 4.50 (br m, 2H), 4.10 (q,J=7.0 Hz, 2H), 2.99 (s, 3H), 2.45 (m, 2H), 1.70-1.50 (m, 8H), 1.24 (t,J=7.0 Hz, 3H)

(iv)3(exo)-(2-Oxo-1,2-dihydro-quinolin-6-ylsulfanyl)-9-aza-bicyclo[3.3.1]nonane-9-carboxylicacid ethyl ester

To a solution of the intermediate from step (iii) (1.34 g, 4.60 mmol),thioacetic acid S-(2-oxo-1,2-dihydro-quinolin-6-yl) ester (98.3 mg, 0.78mmol), cesium fluoride (699 mg, 4.60 mmol) in dry DMF (10 mL),pyrrolidine (654.3 mg, 9.20 mmol) was added at rt. The mixture wasdegassed, heated at 80° C. and stirred overnight under N₂. The reactionwas quenched with water, and filtered to remove the cessium fluorideexcess. The filtrate was extracted with ethyl acetate. The organic layerwas washed with water and brine, and dried on MgSO₄ anh. The solvent wasremoved in vacuo to give the title compound, which was submitted to thenext reaction without further treatment.

Ion Electrospray Mass Spectrum M+1: 373, M−1: 371.

(v) 6-(9-Methyl-9-aza-bicyclo[3.3.1]non-3(exo)-ylsulfanyl)-1-NH-quinolin-2-one

To an ice-cooled solution of the intermediate from step (iv) (536 mg,1.4 mmol) in toluene anhydrous (11 mL), sodium bis(methoxyethoxy)aluminium hydride (Red-Al (3.4 M in toluene)) (1.47 mL, 5.02 mmol) wasadded. The mixture was stirred overnight under N₂ and allowed to reachrt. Once the starting material had disappeared by mass analysis, thesolvent was removed in vacuo. The residue was dissolved in methanol andsubmitted to SCX purification followed by SPE purification. As thedesired product was further purified by reverse phase HPLC in twobatches. For the first batch, formic acid was used in the purificationand 50 mg, 10%, were obtained of the title compound. From the secondone, trifluoroacetic acid was used getting 70 mg, 12% of thecorresponding trifluorooacetate salt. Total yield: 22%

Ion Electrospray Mass Spectrum M+1: 315

¹H NMR (500 MHz, CD₃OD) δ (ppm) for the free amine: 7.96 (d, J=9.5 Hz,1H), 7.87 (d, J=1.5 Hz, 1H), 7.70 (dd, J=8.5 y 1.9 Hz, 1H), 7.37 (d,J=8.5 Hz, 1H), 6.64 (d, J=9.5 Hz, 1H), 3.92 (m, 1H), 3.54 (br, s, 2H),2.90 (s, 3H), 2.24 (m, 6H), 2.04 (m, 1H). 1.92 (m, 2H), 1.73 (m, 1H)

EXAMPLE 72 3-Chloro-4-[(8-methyl-8-azabicylo[3.2.1]oct-3-yl)thio]phenol

By proceeding in a similar manner to Example 9 but using 3-chlorophenolin place of 3-bromophenol in step (i), there was prepared the titlecompound as a colourless solid.

δ_(H) (300 MHz; D6 DMSO) 1.47 (2H, m), 1.58 (4H, m), 1.90 (2H, m), 2.10(3H, s), 3.02 (2H, m), 3.28 (1H, m), 6.75 (1H, m), 6.90 (1H, m); 7.39(1H, m); FIA-MS: 284[(M+H)⁺, 100%].

1. A compound represented by Formula (I) or pharmaceutically acceptablesalts thereof:

wherein: R¹ is —H, C₁₋₂alkyl optionally substituted with 1, 2 or 3groups independently selected from halogen, hydroxyl, thiol, C₁₋₄alkoxyor C₁₋₄alkylthio, or aryl-C₁₋₄alkyl; R² is —H, —OH, —NH₂, —NH-Q-V-T,wherein Q is —C(O)—, —C(O)—NH—, —C(O)O—, or —SO₂—; V is H, aryl,aryl-C₁₋₁₂alkyl, diaryl-C₁₋₁₂alkyl, lactonyl, or C₁₋₁₈alkyl optionallysubstituted with halogen, hydroxyl, C₁₋₄alkoxy, —C(O)OC₁₋₄alkyl,—OC(O)C₁₋₄alkyl, aryl-C₁₋₄alkoxy, aryloxy, or SO₂C₁₋₄alkyl; and T is H,halogen, C₁₋₅alkyl, C₁₋₄alkoxy, nitro, aryl, aryl-C₁₋₄alkyl, or aryloxyunless V is H in which case T is absent, aryl, -(L)_(a)-Z, wherein L isCH₂, CO, O, NH or N(C₁₋₄alkyl) and a is 0 or 1; and Z is C₁₋₃alkyl-F,C₀₋₃alkyl-aryl-R⁶, C₀₋₃alkyl-CO—R⁶, C₀₋₃alkyl-CO—NR⁶ ₂,C₀₋₃alkyl-CO₂—R⁶, C₀₋₃alkyl-SO₂—R⁶, C₀₋₃alkyl-SO₂—NR⁶ ₂, C₁₋₃alkyl-OR⁶,C₁₋₃alkyl-CN or C₁₋₃alkyl-NR⁶ ₂, wherein each C₀₋₃alkyl or C₁₋₃alkylportion is optionally substituted with from 1 to 6 groups selected fromF and C₁₋₅alkyl, linked back to the aromatic ring so as to form a fusedbicyclic compound represented by Formula (Ia)

 wherein D is O or S; and E is O, S, NR⁵, C(R⁵)₂, O—CR⁵ ₂, NR⁵—CR⁵ ₂,NR⁵—CO, CR⁵ ₂—O, CR⁵ ₂—S(O)_(r), CR⁵ ₂—NR⁵, CR⁵ ₂—CR⁵ ₂, CO—NR⁵, orCR⁵═CR⁵; or linked back to the aromatic ring so as to form a fusedbicyclic compound represented by Formula (Ib)

 wherein G is CR⁵ or N; and J is CR⁵ or N; unless X is N in which caseR² is absent R³ is H, halogen, C₁₋₄alkyl optionally substituted withfrom 1 to 3 fluorine atoms, cyano, CF₃, OC₁₋₄alkyl, aryloxy,arylC₁₋₄alkyl, arylC₁₋₄alkoxy, C₃₋₁₀cycloalkoxy, carboxy, carbonamido,—CO—NH—C₁₋₄alkyl, aryl, hydroxy, —SO₂NH₂, —SO₂NHC₁₋₄alkyl, or—C₁₋₄alkyl-OH; R⁴ is H, halogen, C₁₋₄alkyl optionally substituted withfrom 1 to 3 fluorine atoms, cyano, CF₃, OC₁₋₄alkyl, aryloxy,arylC₁₋₄alkyl, arylC₁₋₄alkoxy, C₃₋₁₀cycloalkoxy, carboxy, carbonamido,—CO—NH—C₁₋₄alkyl, aryl, hydroxy, —SO₂NH₂, —SO₂NHC₁₋₄alkyl, or—C₁₋₄alkyl-OH; R⁵ is each independently H or C₁₋₄alkyl; R⁶ is eachindependently H, C₁₋₆alkyl, aryl or arylC₁₋₄alkyl, each of which (exceptH) may be optionally substituted with from 1 to 3 fluorine atoms; X is Cor N; W is C or N; W′ is C or N; Y is C or N; Y′ is C or N; providedthat there are no more than two N atoms in the aryl ring; A is a doublebond; m, n, o and p are independently 0, 1, 2 or 3; q is optionally 1, 2or 3; r is 0, 1 or
 2. provided that when X, W, W′, Y and Y′ are all C,R³ is H, R⁴ is H or Cl positioned meta to the sulphur atom, A is(CH₂)_(q) and R¹ is selected from H, unsubstituted C₁₋₄alkyl andunsubstituted C₃₋₄cycloalkyl; then R² may not be H or —OH, and that whenone of X, Y and Y′ is N, R³ is H, R⁴ is H or Cl positioned meta to thesulphur atom, A is (CH₂)_(q) and R¹ is selected from H, unsubstitutedC₁₋₄alkyl and unsubstituted C₃₋₄cycloalkyl; then R² may not be H or —OH.2. A compound as claimed in claim 1 wherein: R² is —H, —NH₂, —NH-Q-V-Tas defined in claim 1, aryl, -(L)_(a)-Z as defined in claim 1, linkedback to the aromatic ring so as to form a fused bicyclic compoundrepresented by Formula (Ia) as defined in claim 1, or linked back to thearomatic ring so as to form a fused bicyclic compound represented byFormula (Ib) as defined in claim 1; unless X is N in which case R² isabsent.
 3. A compound as claimed in claim 1 wherein: R² is —NH-Q-V-T asdefined in claim 1, aryl, -(L)_(a)-Z as defined in claim 1, linked backto the aromatic ring so as to form a fused bicyclic compound representedby Formula (Ia) as defined in claim 1, or linked back to the aromaticring so as to form a fused bicyclic compound represented by Formula (Ib)as defined in claim 1; unless X is N in which case R² is absent.
 4. Acompound as claimed in claim 1 wherein: R² is —NH-Q-V-T wherein Q is—C(O)—NH—, or —C(O)O—; V is as defined in claim 1; and T is as definedin claim 1;  aryl,  -(L)_(a)-Z as defined in claim 1,  linked back tothe aromatic ring so as to form a fused bicyclic compound represented byFormula (Ia) as defined in claim 1, or  linked back to the aromatic ringso as to form a fused bicyclic compound represented by Formula (Ib) asdefined in claim 1; unless X is N in which case R¹ is absent.
 5. Acompound as claimed in claim 1 wherein: R¹ is —H, C₁₋₁₂alkyl optionallysubstituted with 1, 2 or 3 groups independently selected from halogen,hydroxyl, thiol, C₁₋₄alkoxy or C₁₋₄alkylthio, or aryl-C₁₋₄alkyl; R² is—H, —OH, —NH₂, —NH-Q-V-T, wherein Q is —C(O)—, —C(O)—NH—, —C(O)O—, or—SO₂—; V is aryl, aryl-C₁₋₁₂alkyl, diaryl-C₁₋₁₂alkyl, lactonyl, orC₁₋₁₈alkyl optionally substituted with halogen, hydroxyl, C₁₋₄alkoxy,—C(O)OC₁₋₄alkyl, —OC(O)C₁₋₄alkyl, aryl-C₁₋₄alkoxy, aryloxy, orSO₂C₁₋₄alkyl; and T is H, halogen, aryl, aryl-C₁₋₄alkyl, or aryloxy,unless X is N in which case R² is absent R³ is H, halogen, C₁₋₄alkyl,cyano, CF₃, OC₁₋₄alkyl, aryloxy, arylC₁₋₄alkoxy, C₃₋₁₀cycloalkoxy,carboxy, carbonamido, —CO—NH—C₁₋₄alkyl, aryl, hydroxy, —SO₂NH₂,—SO₂NHC₁₋₄alkyl, or —C₁₋₄alkyl-OH, R⁴ is H, halogen, C₁₋₄alkyl, cyano,CF₃, OC₁₋₄alkyl, aryloxy, arylC₁₋₄alkoxy, C₃₋₁₀cycloalkoxy, carboxy,carbonamido, —CO—NH—C₁₋₄alkyl, aryl, hydroxy, —SO₂NH₂, —SO₂NHC₁₋₄alkyl,or —C₁₋₄alkyl-OH, X is C or N, W is C or N, provided that both X and Yare not N, W′is C Y is C or N Y′is C A is a double bond; m, n, o and pare independently 0, 1, 2 or 3 q is optionally 1, 2 or 3 r is
 0. 6. Acompound as claimed in claim 5 wherein R¹ is H, C₁₋₆alkyl optionallysubstituted with 1 or 2 hydroxyl groups, or aryl-C₁₋₄alkyl.
 7. Acompound as claimed in claim 6 wherein R¹ is benzyl, p-methoxybenzyl,furanylmethyl, imidazolylmethyl, pyridinylmethyl, thienylmethyl,pyridylmethyl, N-hydroxypyridylmethyl or thiazolylmethyl.
 8. A compoundas claimed in claim 5 wherein R² is H, R³ is carbonamido (—CONH₂) orC₁₋₄alkyl-OH, and R⁴ is H, C₁₋₄alkyl, CF₃, halogen or cyano.
 9. Acompound as claimed in claim 5 wherein R² is OH, and R³ and R⁴ eachindependently represent H, C₁₋₄alkyl, CF₃, cyano or halogen.
 10. Acompound as claimed in claim 5 wherein R² is of formula —NH-Q-V-T; T isH and R³ and R⁴ each independently represent H, methyl, CF₃, chloro- orcyano-.
 11. A compound as claimed in claim 5 wherein R² is of formula—NH—SO₂—V-T; V is aryl, —C₁₋₁₂alkyl or aryl-C₁₋₁₂alkyl; R₃ is H, methyl,CF₃, Cl or cyano and R⁴ is H.
 12. A compound as claimed in claim 5wherein R² is of formula —NH—SO₂—V-T, V is selected from C₁₋₁₂alkyl,phenyl, naphthyl, thienyl, oxazolyl, isoxazolyl, or phenyl(CH═CH),optionally substituted with 1, 2, 3 or 4 substituents selected from:—NO₂; halogen; —CF₃; C₁₋₁₂alkoxy; C₁₋₁₂alkylthio; C₁₋₁₂alkyl;C₁₋₄alkylsulfonyl; —CN; —OCF₃; —C(O)OC₁₋₄alkyl; —OCH₂CF₃;—NHC(O)C₁₋₄alkyl.
 13. a compound as claimed in claim 5 wherein R² is offormula —NH—SO₂—V-T, T is selected from H; or diazole, oxazole,isoxazole, phenyl or phenoxy, optionally substituted with 1, 2, 3 or 4substituents selected from —NO₂; halogen; —CF₃; C₁₋₁₂alkoxy;C₁₋₁₂alkylthio; C₁₋₁₂alkyl; C₁₋₄alkylsulfonyl; —CN; —OCF₃;—C(O)OC₁₋₄alkyl; —OCH₂CF₃; —NHC(O)C₁₋₄alkyl.
 14. A compound as claimedin claim 5 wherein R² is of formula —NH—SO₂—V-T, V is selected from3-chloro-4-methylphenyl, 3-chlorophenyl, 3-methoxyphenyl, 4-bromophenyl,4-methoxyphenyl, 4-methylphenyl, naphthyl, 2,4,6-trimethylphenyl,phenyl(CH═CH)—, 4-chlorophenyl, 2-chlorophenyl, 2,5-dichlorothien-3-yl,2,5,6-trimethyl-4-methoxyphenyl, 4-methoxyphenyl, 2,3,4-trifluorophenyl,3-cyanophenyl, 2-methoxycarbonylthien-3-yl or 4-pentylphenyl and T is H.15. A compound as claimed in claim 5 wherein R² is of formula—NH—SO₂—V-T, T is 2-chloro-5-nitrophenoxy and V is phenyl.
 16. Acompound as claimed in claim 5 wherein R² is of formula —NH—C(O)—V-Twherein V is selected from aryl; aryl-C₁₋₁₂alkyl; diaryl-C₁₋₁₂alkyl;lactonyl; or Cl₁₋₈alkyl optionally substituted with halogen, hydroxyl,C₁₋₄alkoxy, C(O)OC₁₋₄alkyl, OC(O)C₁₋₄alkyl, aryl-C₁₋₄alkoxy or aryloxy.17. A compound as claimed in claim 5 wherein R² is of formula—NH—C(O)—V-T, and V is selected from C₁₋₁₂alkyl, phenyl,phenyl-C₁₋₁₂alkyl, diphenylmethyl, naphthyl, furanyl, thienyl, diazolyl,pyridinyl, thiazolyl, benzothienyl, fluorenyl, oxazolyl or isoxazolyl,optionally substituted with 1, 2, 3 or 4 substituents independentlyselected from —NO₂; halogen; —CF₃; C₁₋₁₂alkoxy; C₁₋₁₂alkylthio;C₁₋₁₂alkyl; C₁₋₄alkylsulfonyl; —CN; —OCF₃; —C(O)O—C₁₋₄alkyl; —OCH₂CF₃.18. A compound as claimed in claim 5 wherein R² is of formula—NH—C(O)—V-T, T is selected from H; halogen; or diazole, oxazole,isoxazole, phenyl, phenoxy or benzodioxanyl optionally substituted with1, 2, 3 or 4 substituents selected from —NO₂; halogen; —CF₃;C₁₋₁₂alkylthio; C₁₋₁₂alkoxy; C₁₋₁₂alkyl; C₁₋₄alkylsulfonyl; —CN; —OCF₃;—C(O)O—C₁₋₄alkyl.
 19. A pharmaceutical composition comprising a compoundas claimed in claim 1 with a pharmaceutically acceptable diluent orcarrier.
 20. A method of treatment of dysfunctions of the central andautonomic nervous systems comprising administering an effective amountof a compound of claim 1 to a patient in need thereof.